Double Blind Randomized Placebo-Controlled Trial Comparing the Effects of Anti-thrombin vs Placebo on the

Coagulation System in Infants with Anti-Thrombin Deficiency Undergoing Congenital Cardiac Surgery

Rebecca Scholl, MD1, Claudia Benkwitz, MD2, Manuel Fontes, MD3, Nirmish Shah, MD4, Robert Jaquiss, MD5, Andrew Lodge, MD5, Warwick Ames, MD1, Hercilia Homi, MD1, Kelly Machovec, MD1, Edmund Jooste, MD1

1Division of Pediatric Cardiac Anesthesia, 4Division of Hematology, 5Division of Congenital Cardiac Surgery, Duke University Medical Center, Durham, NC 27710, USA2Division of Pediatric Anesthesia, Department of Anesthesiology, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, TN 37232, USA

3Division of Cardiac Anesthesia, Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06510, USA

Extraordinary Care –

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Introduction

• Anti-thrombin III (ATIII) plays a critical role in achieving

adequate heparinization for cardiopulmonary bypass

(CPB) and preventing vascular thrombosis.

• It is recognized that neonates and infants, less than 7

months, have decreased ATIII.

• Insufficient ATIII levels in infants undergoing congenital

heart surgery may be responsible for the increased

frequency of heparin resistance, consumptive

coagulopathy from deficient anticoagulation, and

postoperative thrombotic events in this population.

Methods

• Randomized, double blinded, placebo

controlled study

• 2 academic centers

• Inclusion

• Infants < 7 months

• Cardiac surgery requiring CPB

• ATIII < 70%

• Exclusion

• < 2.5 kg

• Hereditary ATIII deficiency

• ECMO at time of surgery

• History of thrombosis

• Renal failure

• Prematurity < 37 weeks GA

• History intracranial hemorrhage

• Prior ATIII supplementation

• Prior therapeutic anticoagulant use

• Units required =

100% −𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐴𝑇𝐼𝐼𝐼 𝑙𝑒𝑣𝑒𝑙 𝑥 % 𝑥 𝑏𝑜𝑑𝑦 𝑤𝑡

1.4

• Recorded

• Demographics

• Laboratory values

• Heparin and protamine doses

• Hemostatic agents

• Blood products administered

• Operating room times

• 24 hour chest tube output

• Occurrence of postoperative thrombosis

Table 1. Demographics and Perioperative Variables

AT Group

(n=20)

Placebo Group

(n=19)p Value

Age (days) 9.8 ± 19.7 17.2 ± 30.2 0.174

Gender (M:F) 14:06 13:06 0.915

Weight (kg) 3.4 ± 0.5 3.5 ± 0.6 0.792

Aristotle score level 0.304

Level 2 (includes Aristotle scores 6.0-7.9) 3 (15.0 %) 1 (5.3%)

Level 3 (includes Aristotle scores 8.0-9.9) 7 (35.0%) 4 (21.1%)

Level 4 (includes Aristotle scores 10.0-15.0) 10 (50.0%) 14 (61.5%)

ACT baseline (sec) 129 ± 22 120 ± 13 0.141

Pre CPB Heparin dose determined by HMS machine (U/kg) 532 ± 64 602 ± 154 0.106

ACT post heparin (sec) 740 ± 221 583 ± 127 0.041

Heparin dosing – Total on CPB (U) 4372 ± 1627 5520 ± 1924 0.055

Total CPB time (min) 185 ± 60 212 ± 66 0.186

Total Cross clamp time (min) 87.4 ± 54 101.4 ± 32 0.329

Protamine dose determined by HMS machine (mg/kg) 11 ± 7.6 9.3 ± 2.8 0.545

Protamine to chest closure time (min) 109.8 ± 56.5 105.1 ± 59 0.757

Chest Tube output (protamine time plus 24 hrs) (mls) 74.9 ± 50 138 ± 94 0.016

Exposure to any Blood products in 24h Postop (n) 6 11

Total 24h Postop Blood product unit exposures (n) 6 19 0.000003

24h Postop FFP Unit exposures (n) 1 3

24h Postop Platelet Unit exposures (n) 0 4

24h Postop Cryo-precipitate Unit exposures (n) 0 3

24 Postop Red Blood cell Unit exposures (n) 5 9

Major Adverse Events 8 8 0.894

Introduction: Anti-thrombin (AT) is crucial for heparin to be effective1

and for the prevention of thrombosis2 and levels are known to be low in

infants. We tested the hypothesis that pre cardiopulmonary bypass

(CPB) normalization of AT levels to 100% would improve anticoagulation

during CPB, attenuate activation of the coagulation cascade, as

measured by fibrin degradation products- D-Dimers, and mitigate micro-

thrombosis in the post-operative period.

Methods: This is a randomized, double blinded, placebo controlled study

in infants with AT levels less than 70% undergoing CPB at 2 academic

centers. Half were given AT (Thrombate®) to normalize to 100%

functional assay and the other half received placebo. We recorded

demographics, laboratory values, hemostatic agents, blood products

administered, operating room times, 24-hour chest tube output, and

occurrence of post-operative thrombosis. Summary statistics, pooled T-

test, Fisher exact test and Wilcoxon Rank-Sum test were performed-

Data are represented as percentage or mean +/- SD, with statistical

significance defined as p<0.05.

Results: Over a 24 month period, 223 patients were screened; 68 met

inclusion criteria, 40 were randomized, and 1 (in Placebo group) was

withdrawn during the study due to ECMO initiation in the operating room.

Thirty percent of screened patients had AT levels <70%. Table 1 shows

demographic and peri-operative variables. Notable differences were

observed between the two groups including higher first post-heparin

activated clotting time (ACT) and AT levels in the treatment group. Table

2 shows Laboratory results. No differences were noted between the 2

groups with CPB circuit red blood cell and FFP prime usage, or

intraoperative blood, platelet, cryoprecipitate, recombinant Factor VIIa

and Prothombin Complex Concentrate usage. Significantly, 24 hours

post-operative chest tube output, overall blood product transfusions and

D-Dimer production were all lower in the AT group. No difference in

major adverse events (significant bleeding, stroke, allergic reaction,

ECMO initiation, chest exploration or death) was noted.

Conclusion:

Replacement of AT improves anticoagulation during CPB without

increased rates of bleeding or adverse events. Furthermore our results

suggest extension of these beneficial effects into the postoperative

period, reflected by significantly less postoperative bleeding and

transfusions, and generation of D-Dimers. We conclude that treatment of

low AT levels with exogenous AT is helpful in infants undergoing cardiac

surgery on CPB.

Results

• 24 month period, screened 223 patients

• 30% patients had ATIII <70% (68 met inclusion criteria)

• 40 randomized (1 placebo group withdrawn due to

ECMO initiation in OR)

• Demographics and Perioperative Variables (Table 1)

• Treatment group demonstrated higher:

• First post-heparin activated clotting time (ACT)

• ATIII levels (persisted into early ICU stay)

• Measured sensitive biomarkers for ongoing coagulation and

fibrinolytic system activation (Table 2)

• No differences:

• CPB circuit RBC and FFP prime usage

• Intraoperative blood, platelet, cryoprecipitate,

recombinant Factor VIIa and Prothrombin

Complex Concentrate usage

• Significant differences: Treatment group showed lower:

• 24 hour postoperative chest tube output

• Overall blood product transfusion

• D-dimer production

• POD 4: reflecting attenuation of coagulation

cascade during CPB resulting in less

fibrinolysis

• No difference

• Major adverse events: Significant bleeding, stroke,

allergic reactions, ECMO initiation, chest

exploration or death.

Table 2. Study Lab Values

Time Point ATIII Group (n=20)Placebo Group

(n=19)p Value

ATIII functional assay (%) T1 (Baseline) 54 ± 12 54 ± 13 0.982

ATIII functional assay (%) T2 (30 min after study drug) 99 ± 19 49 ± 16 <0.0001

ATIII functional assay (%) T3 (30 min on CPB) 83 ± 20 55 ± 27 0.0007

ATIII functional assay (%) T4 (just prior to coming off CPB) 87 ± 34 63 ± 28 0.048

ATIII functional assay (%) T5 (Arrival in ICU) 82 ± 18 63 ± 19 0.003

ATIII functional assay (%) T6 (POD 2) 58 ± 15 57 ± 14 0.84

ATIII functional assay (%) T7 (POD 4) 70.7 ± 20 66 ± 17 0.475

D Dimer (mcg/ml) T1 (Baseline) 1.2 ± 0.8 1.3 ± 0.8 0.855

D Dimer (mcg/ml) T5 (Arrival in ICU) 1.0 ± 0.9 1.3 ± 1 0.225

D Dimer (mcg/ml) T6 (POD 2) 1.5 ± 1 2.3 ± 2 0.313

D Dimer (mcg/ml) T7 (POD 4) 3.6 ± 1.7 6.8 ± 4.2 0.008

Conclusion

• ATIII replacement to 100%

• Improved anticoagulation during CPB

• No increased rates of intraoperative bleeding or

adverse events

• Beneficial effects persisted in postoperative period

• Less bleeding

• Decreased blood product transfusion

• Reduced fibrinolysis (D-Dimers)

• Normalization of ATIII with exogenous AT is helpful in

infants undergoing cardiac surgery on CPB.

Results represented by Mean ± SD. HMS machine – Hemostasis Management System machine; CPB – cardiopulmonary bypass; AT – Anti-Thrombin; Postop -

Postoperative

Purpose

• Normalization of ATIII levels to 100% pre

cardiopulmonary bypass in infants undergoing

congenital cardiac surgery would result in:

• Improved anticoagulation for CPB

• Decreased total heparin and protamine

dose

• Less intraoperative bleeding due to

attenuation of coagulation cascade

• Decreased thrombosis in postoperative

period