Authors Accepted Manuscript

Antifibrinolytic agents in cardiac and non-cardiac

surgery a comprehensive overview and update

Neal S. Gerstein, Janet K. Brierley, Jimmy

Windsor, Pramod V. Panikkath, Harish Ram, Kirill
M. Gelfenbeyn, Lindsay J. Jinkins, Liem C.
Nguyen, Wendy H. Gerstein
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PII: S1053-0770(17)30079-4
DOI: http://dx.doi.org/10.1053/j.jvca.2017.02.029
Reference: YJCAN3994
To appear in: Journal of Cardiothoracic and Vascular Anesthesia
Cite this article as: Neal S. Gerstein, Janet K. Brierley, Jimmy Windsor, Pramod
V. Panikkath, Harish Ram, Kirill M. Gelfenbeyn, Lindsay J. Jinkins, Liem C.
Nguyen and Wendy H. Gerstein, Antifibrinolytic agents in cardiac and non-
cardiac surgery a comprehensive overview and update, Journal of
Cardiothoracic and Vascular Anesthesia,
http://dx.doi.org/10.1053/j.jvca.2017.02.029
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 Antifibrinolytic agents in cardiac and non-cardiac surgery a comprehensive overview and update

1) Neal S. Gersteina, MD FASE

Title: Associate Professor of Anesthesiology
Email: ngerstein@gmail.com
a
Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of
Medicine, MSC 10 6000, 2211 Lomas Blvd NE, Albuquerque, New Mexico 87106 USA

2) Janet K. Brierleya, MBBS FRCA

Title: Professor of Anesthesiology
Email: jbrierley@salud.unm.edu
a
Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of
Medicine, MSC 10 6000, 2211 Lomas Blvd NE, Albuquerque, New Mexico 87106 USA

3) Jimmy Windsora MD
Title: Associate Professor of Anesthesiology
Email: JWindsor@salud.unm.edu
a
Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of
Medicine, MSC 10 6000, 2211 Lomas Blvd NE, Albuquerque, New Mexico 87106 USA

4) Pramod V. Panikkatha MD
Title: Assistant Professor of Anesthesiology
Email: PPanikkath@salud.unm.edu
a
Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of
Medicine, MSC 10 6000, 2211 Lomas Blvd NE, Albuquerque, New Mexico 87106 USA

5) Harish Rama MD
Title: Assistant Professor of Anesthesiology
Email: hram@salud.unm.edu
a
Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of
Medicine, MSC 10 6000, 2211 Lomas Blvd NE, Albuquerque, New Mexico 87106 USA

6) Kirill M. Gelfenbeyna DO
Title: Resident physician
Email: KGelfenbeyn@salud.unm.edu
a
Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of
Medicine, MSC 10 6000, 2211 Lomas Blvd NE, Albuquerque, New Mexico 87106 USA

7) Lindsay J. Jinkinsa MD
Title: Resident physician
Email: LJJinkins@salud.unm.edu
a
Department of Anesthesiology and Critical Care Medicine, University of New Mexico School of
Medicine, MSC 10 6000, 2211 Lomas Blvd NE, Albuquerque, New Mexico 87106 USA

8) Liem C. Nguyenb MD
Title: Associate Professor of Anesthesiology
Email: lcn002@ucsd.edu
b
University of California San Diego Medical Center and Sulpizio Cardiovascular Center

1
Department of Anesthesiology; Division of Cardiothoracic Anesthesiology - UC-San Diego, San Diego,
California 92037USA

9) Wendy H. Gersteinc MD
Title: Professor of Medicine
Email: wgerstein@gmail.com
c
Department of Internal Medicine, Raymond G. Murphy VA Medical Center, Albuquerque, New Mexico
87108 USA

Funding: None

Disclosures: None

Corresponding Author:
Neal Stuart Gerstein MD FASE
Department of Anesthesiology and Critical Care Medicine
University of New Mexico School of Medicine - MSC 10 6000
2211 Lomas Blvd NE
Albuquerque, NM 87106
Tel 505-272-2610
Fax 505-272-1300
ngerstein@gmail.com

2
Neal S. Gerstein MD FASE

Department of Anesthesiology & Critical Care Medicine Division of Cardiac Anesthesia

University of New Mexico School of Medicine

MSC 10 6000

1 University of New Mexico

Albuquerque, NM 87131

Office 505 272 2610

Fax 505 272 1300

ngerstein@gmail.com

Antifibrinolytic agents in cardiac and non-cardiac surgery a comprehensive overview and update

Introduction

Employing strategies to mitigate blood loss and the need for transfusion is a fundamental

component of caring for surgical patients. Antifibrinolytic use is standard practice for complex cardiac

surgery and cardiac surgery involving cardiopulmonary bypass (CPB). The most recent Society of

Thoracic Surgeons (STS) and Society of Cardiovascular Anesthesiologists (SCA) Blood Conservation

Clinical Practice Guidelines give their highest recommendation (IA) for the use of antifibrinolytics in

cardiac surgery.1 Outside the context of cardiac surgery, the use of antifibrinolytics in the perioperative

period to reduce blood loss and minimize allogeneic transfusion requirements has burgeoned in the past

decade.2 Antifibrinolytic agent use is now included in the 2015 World Health Organization (WHO) list of

essential medicines,3 multiple trauma management protocols,4, 5 postpartum hemorrhage (PPH)

prevention and treatment,6, 7 as well as in a broad range of other surgical specialties (hepatobiliary,8, 9

orthopedic,10 neurologic,11 obstetric/gynecologic,12 urologic,13 vascular,14 pediatric).15 As the use of

antifibrinolytics has increased in both non-cardiac and cardiac surgery, concerns have been raised

regarding the potential serious adverse effects of these hemostatic agents and their safe clinical use.

Antifibrinolytics comprise a group of pharmacologic agents that include: epsilon-aminocaproic

acid ((EACA), tranexamic acid (TXA), and aprotinin. This review and update will focus on the

3
background, uses in cardiac and major non-cardiac surgery (particularly for EACA and TXA), costs, as well

as precautions and concerns associated with each antifibrinolytic agent.

Epsilon aminocaproic acid

EACA (Amicar, Clover Pharmaceuticals, Marietta, GA) is a highly water soluble, colorless crystal

that is one of two currently available synthetic lysine analogues. Both lysine analogues (EACA and TXA)

act to block plasminogens conversion to plasmin leading to a resultant inhibiting in fibrinolysis. See

Figure 1 for EACAs chemical structure and Figure 2 for a detailed description and schematic of its

mechanism of action.

Epsilon aminocaproic acid - history and development

EACA was first studied in the laboratory setting dating as far back as 1914, but research in

humans increased in the late 1950s when Japanese researchers tested its use for the treatment of

various ailments (dysmenorrhea, emesis gravidarum, toxemia of pregnancy) in which EACA was

efficacious with minimal side effects.16 Fibrinolytic activity was not measured at that time but

subsequent studies showed that EACA acted as a potent inhibitor of plasminogen activation and

investigators quickly recognized the potential of EACA for controlling bleeding in different clinical

scenarios including surgery.17 In the 1960s EACA was first used in prostatectomy surgery based on

research done by Sack et al18, which showed a clinically significant reduction in blood loss in 18 patients

treated with a continuous EACA infusion compared to 18 patients receiving placebo. EACA was

approved by the United States (US) Food and Drug Administration (FDA) in 1964.

Epsilon aminocaproic acid mechanism of action and pharmacokinetics (See Figure 2)

Typically, the proteolytic serum enzyme plasmin hydrolyses polymerized fibrin resulting in

fibrinolysis and dissolution of fibrin clot. EACA modulates the fibrinolytic pathway in the intravascular

space by reversibly binding to the lysine-binding sites of plasminogen (the zymogen precursor of

plasmin). Due to EACAs structural similarity to lysine (See Figure 1), it is able to bind competitively to

4
the tissue plasminogen activator (TPA) / plasminogen / plasmin complex, inhibiting the binding of this

complex molecule onto fibrin. EACAs binding inhibition prevents plasmin release and inhibits

fibrinolysis, thereby enhancing hemostasis.19

EACAs Vd is 30 L with intravenous (IV) administration with peak serum concentrations reached

in approximately 10 minutes.20 After prolonged administration, EACA distributes throughout both intra

and extravascular compartments and penetrates red blood cells and other tissue cells. It is unknown

whether EACA crosses the placenta or is distributed in breast milk,8 but there is evidence it does cross

the blood-brain barrier.21 EACA is primarily excreted via the kidneys with 65% of the unchanged drug

present in urine. Renal clearance approximates creatinine clearance (116 ml/min) with a terminal

elimination half-life of two hours. Total body clearance is markedly decreased in patients with renal

failure and there is evidence it is only partially removed (25%) by hemodialysis and peritoneal dialysis.22

Of note, EACA clearance is reduced in neonates compared to older children and adults.23, 24

Epsilon aminocaproic acid - use in cardiac surgery

EACA has been shown to be effective in reducing bleeding and transfusion needs associated

with cardiac surgery involving CPB in adults.25, 26 In Mangano et als25 observational study of 4374

patients undergoing myocardial revascularization, the three antifibrinolytics (aprotinin, EACA, TXA) were

prospectively assessed with regard to drug efficacy and serious adverse outcomes. All agents were

effective in reducing perioperative blood loss and the authors concluded that EACA and TXA were safe

alternatives to aprotinin.25 A 2007 meta-analysis comparing all three antifibrinolytic agents during

cardiac surgery demonstrated that EACA is effective in reducing blood loss and transfusion needs when

used prophylactically without increased adverse effects.27 In 2008, the Blood conservation using

Antifibrinolytics: Randomized Trial (BART) was published which at the time was the largest randomized

multicenter blinded trial comparing aprotinin, TXA, and EACA.28 BART was a blinded multicenter RCT

comparing the three agents in high-risk (procedures with an average risk of death at least twice that

5
expected for isolated primary coronary artery bypass grafting (CABG)) cardiac surgery patients. BART

assigned 2331 high-risk cardiac surgical patients undergoing CPB to one of three groups: 781 received

aprotinin, 770 received TXA, and 780 received EACA. The primary outcome was postoperative bleeding

with a secondary outcome of 30-day mortality. Results demonstrated that all three agents decreased

postoperative bleeding with the trial terminated early due to a higher rate of death in the aprotinin

group (relative risk 1.53, 95% CI 1.06-2.22).28 Using BART-derived data, Raghunathan et al29 compared

TXA and EACA using a clinical value analysis to include clinical outcomes, costs, satisfaction with care,

and functional status; there were no significant differences in overall safety and efficacy between the

two drugs.29

In a 2011 Cochrane review of randomized controlled trials (RCTs), 11 cardiac surgery-specific

(out of 16 total trials) of EACA versus control provided data in a 649 patients (338 EACA versus 311

controls) demonstrated that the use of EACA significantly reduced the need for allogeneic blood

transfusion by a relative 30% (relative risk (RR), 0.70; 95% CI, 0.52 - 0.93).30 Mortality appeared to be

unaffected by treatment with any of the antifibrinolytic drugs and the lysine analogues were free of

serious adverse effects.30 In a 2013 prospective RCT of 64 adult patients undergoing thoracic aortic

surgery with CPB, both EACA and TXA were effective in reducing blood loss and transfusion

requirements.31 Similarly, a 2014 single-center, retrospective observational cohort study (n=120)

comparing TXA and EACA in cardiac surgery with or without CPB found that massive bleeding (defined as

a composite of chest tube drainage > 1,500 mL in any 8-hour period after surgery, perioperative

transfusion of 10 units of red cells, reoperation for bleeding, or death from hemorrhage within 30

days) occurred in 10 patients (16.7%) in the TXA group compared with 5 patients (8.3%) in the EACA

group (p=0.17).32 There were no significant differences in efficacy and 30-day all-cause mortality,

thromboembolic events, renal dysfunction, and seizure. Thus, prophylactically administered EACA has

been demonstrated to be efficacious in reducing both intraoperative and postoperative blood loss and

6
the need for allogenic blood transfusion in patients undergoing routine and high risk cardiac surgery. In

the most recent 2015 American Society of Anesthesiology (ASA) Task Force on Perioperative Blood

Management, EACA was given a Category A1 level of evidence for its use in major cardiac surgery.33

Epsilon aminocaproic acid - use in off-pump coronary artery bypass surgery

Despite avoiding the CPB machine, there is still evidence for the activation of the fibrinolytic

pathway in off-pump CABG (OPCAB) surgery, albeit to a lesser degree compared to on-CPB

procedures.34-36 Though the STS/SCA blood conservation guidelines give antifibrinolytic use a IA

recommendation in cardiac surgery, the guidelines do not provide a definitive specification for their use

in OPCAB procedures.1 Bleeding and the need for blood transfusion still represent important factors for

adverse outcome, with a large percentage of patients still requiring blood component therapy during

OPCAB.37 Hence, it stands to reason that patients at risk for increased bleeding (recent antiplatelet

agent use) or patients where increased bleeding may be of greater consequence (i.e. Jehovahs Witness,

reoperation, pre-existing severe anemia) may benefit from the use of an antifibrinolytic during OPCAB.38

Unfortunately, data on the clinical use of antifibrinolytics in OPCAB is limited to TXA and aprotinin

(discussed below). There are no randomized placebo controlled studies to date on the use of EACA in

OPCAB, making its clinical recommendation difficult for procedures without bypass.

Epsilon aminocaproic acid non-cardiac surgery

Orthopedic surgery

In the context of joint replacement surgery, EACA has demonstrative efficacy. A recent

retrospective analysis using cohort controls in primary total hip arthroplasty (THA) cases demonstrated

EACA efficacious in reducing transfusion requirements (EACA 6.8% vs control 24.7%, p<0.0001).39 Huang

et al40 in a systematic review and meta-analysis demonstrated that EACA significantly reduces blood loss

and blood transfusion requirements while not increasing the risk of deep venous thrombosis (DVT) in

patients undergoing THA. A number of other reports have shown that EACA reduces intraoperative and

7
postoperative blood loss when used IV in THA and total knee arthroplasty (TKA) procedures.41-44 In spine

surgery, a number of recent studies including large systematic reviews confirm that EACA effectively

reduces blood loss and transfusion requirements.45-49 One of these reviews, examining publications

between 1990 and 2009, was conducted to determine the definition and incidence of significant

hemorrhage in adult spine surgery and to assess the efficacy of antifibrinolytic use in this context. The

authors found that of the examined interventions (antifibrinolytics, recombinant Factor VIIa (rFVIIa),

platelet gel, cell salvage, normovolemic hemodilution, controlled hypotension, staged procedures), the

use of TXA or EACA had superior efficacy and concluded that one of these agents should be used

routinely to reduce major hemorrhage in spine surgery.46 In another prospective double-blind RCT, 51

patients undergoing spinal fusion of at least a five levels were randomized to one of three treatment

groups: TXA, EACA, and placebo. There was a significant reduction in total blood loss using EACA versus

control (p=0.007) and EACA had significant reductions in total transfusions versus both TXA and placebo

when controlling for number of levels fused (p=0.42, p=0.021, respectively).45 In a 2015 meta-analysis of

on the use of antifibrinolytics in scoliosis surgery, as compared to placebo, all three antifibrinolytics

significantly reduced perioperative blood loss and transfusion requirements. No comparisons or

analyses were made between the three agents themselves. In a subgroup analysis, intraoperative blood

loss and transfusion rates were superior for TXA and aprotinin as compared to placebo. There were no

findings that the use of an antifibrinolytic agents was a risk factor for adverse events, especially

thromboembolism, in scoliosis surgery.50

Subarachnoid hemorrhage

Rebleeding is one of the most serious complications following aneurysmal SAH (aSAH) leading to

significant morbidity and mortality. The risk for rebleeding is highest within the first 24 hours after aSAH

with a peak in the first six hours.51 Antifibrinolytics have demonstrative efficacy in mitigating rebleeding,

however, their overall impact on outcome is tempered by the risk of sinus thrombosis and delayed

8
ischemia.52, 53 The most recent (2012) American Stroke Association guidelines state: For patients with

an unavoidable delay in obliteration of aneurysm, a significant risk of rebleeding, and no compelling

medical contraindications, short-term (< 72 hours) therapy with TXA or EACA is reasonable to reduce the

risk of early aneurysm rebleeding.54 A 2013 Cochrane review on this topic included 10 studies involving

1904 patients. It demonstrated that short-term treatment (< 72 hours) reduced the risk of re-bleeding

(RR, 0.65; 95% CI 0.44 - 0.97) but noted there was heterogeneity (I = 62%) between the trials. Also, the

pooled RR for cerebral ischemia was 1.41 (95% CI, 1.04 - 1.91) but with no effect on the reported rate of

hydrocephalus. It was concluded that though the short-term treatment may be efficacious, the current

findings do not support routine use of antifibrinolytics in aSAH.53 The current recommendations from

the Neurocritical Care Society's Multidisciplinary Consensus Conference on management of aneurysmal

SAH states: 1) An early, short course of antifibrinolytic therapy prior to early aneurysm repair (begun at

diagnosis; continued up to point at which the aneurysm is secured or at 72 hr post-ictus, whichever is

shorter) should be considered (Low Quality Evidence; Weak Recommendation) and 2) delayed (> 48 hr

after the ictus) or prolonged (> 3 days) therapy exposes patients to side effects of therapy when the risk

of rebleeding is sharply reduced and should be avoided (High Quality Evidence; Strong

Recommendation); they also give a strong recommendation to avoid use in any patient with

thromboembolic risks along with careful observation for potential thrombotic complications.55 The

ULTRA Trial, examining 24-hour maximum use of TXA, should help clarify the role of antifibrinolytics to

prevent rebleeding in aSAH (see TXA section).56

Hepatobiliary surgery

A meta-analysis of 23 trials between 1993 and 2005 found only one trial including EACA.57 They

concluded that both TXA and aprotinin reduced blood transfusion without evidence for an increased risk

of graft thrombosis and stated that the use of EACA could not be recommended, because of limited

evidence.57 A more recent study compared clinical outcomes for a large number of liver transplant

9
patients receiving intraoperative EACA, aprotinin, or no agent over an 8-year period.58 In addition to

decreased intraoperative blood loss, a trend toward improved graft and patient survival was seen in

patients receiving EACA. A retrospective, observational, single-center cohort study of 708 adult liver

transplantations performed from 2008 to 2013, examined the role of EACA administered after

reperfusion of the donor liver for the incidences of thromboembolic events, acute kidney injury within

30 days, and one-year survival. None of the analyzed cases involved the use of veno-venous bypass and

the decision to administer EACA was based upon the presence of hyperfibrinolysis determined using

thromboelastography both important limitations of this study. Essentially, EACA was administered on

as needed basis. EACA use did not reduce the need for transfusion, was also not associated with an

increased incidence of thromboembolic complications or postoperative acute kidney injury (AKI), and it

did not alter 1-year survival after liver transplantation.59 EACA use in major liver surgery is also given a

Category A1 recommendation by the ASA Task Force on Perioperative Blood Management.33

Trauma

There is a paucity of data on the specific use of EACA in the setting of major bleeding and

coagulopathy following trauma. The vast majority of literature relates to TXA (see TXA section). The

most recent Cochrane review on antifibrinolytic drug use in acute traumatic injury mentions EACA as an

agent but the review included trials involving only TXA and aprotinin. The authors reached the

conclusion that TXA was the recommended therapy.60 European guidelines on the management of

major bleeding and coagulopathy following trauma recommends EACA as a potential alternative, if TXA

is unavailable.61 This seems to be a reasonable option based on similar mechanism of action, efficacy,

and safety in trials involving major surgical procedures.

Epsilon aminocaproic acid dosing and timing of administration

EACA is most commonly administered IV though topical application at the surgical site has been

reported.62, 63 The plasma concentration of EACA required to inhibit fibrinolysis in-vitro is 130 g/ml.64

10
There is no standard guideline for EACA dosing and several dosing regimens have been used in trials.

See Table 1 for common dosing strategies in cardiac and non-cardiac surgery. In cardiac surgery, a

loading dose of 70 mg/kg post-heparin administration combined with an infusion of 30 mg/kg/h

generates a blood concentration of 260 mg/L (approximately double the needed concentration to inhibit

in-vitro fibrinolysis).65 A comparison of EACA administered before and after heparin to placebo revealed

that both EACA protocols reduced chest tube drainage.66 Thus, EACA loading dose may be administered

either at the time of induction or after anticoagulation for CPB but before initiation of CPB. At the

authors institution in cardiac surgery, no antifibrinolytic is administered for OPCAB procedures unless

there is recent anti-platelet use, repeat sternotomy, or the patient refuses blood product

administration. For procedures involving CPB, EACA is our agent of choice with dosing based upon the

protocol by Greilich et al.67 TXA is our primary agent used in non-cardiac surgery.

Epsilon aminocaproic acid safety and precautions

Overall, EACA is well tolerated. Due to its action on the fibrinolytic pathway, there is the

potential for generating a prothrombotic state with resultant thromboembolic complications. There are

no trials or high volume reports indicating that EACA has significantly worrisome thrombotic potential

relative to TXA or aprotinin. Like any prothrombotic procoagulant drug, appropriate caution must be

undertaken when considering administering any antifibrinolytic agent. For a list of various clinical

scenarios and associated precautions and risks when using EACA, see Table 2. In terms of reported

EACA-related thrombotic complications, most of the literature consists of isolated reports and most

clinical trials are not powered to detect thrombotic events occurring in treatment versus control arms.

Two fatal massive intraoperative thrombosis cases were reported following use of EACA in patients

undergoing aortic surgery (ascending aneurysm repair, Bentall procedure). Post-mortem analysis

revealed Factor V Leiden mutation in one of the two cases; aside from this underlying hypercoagulable

state, the authors attributed the lethal post-CPB thrombosis to a combination of low-level disseminated

11
intravascular coagulation (DIC) - associated hypothermic CPB, EACA itself, possible low heparin

concentrations, and the graft material.68 Other sporadic reports include a nonfatal case in a patient

undergoing cardiac surgery69 and a nonfatal superior sagittal and left transverse sinus thrombosis during

outpatient menorrhagia management.70 Intracardiac thrombi and pulmonary embolus have also both

been described in orthotopic liver transplantation (OTL) while using EACA.71

In a recently presented abstract, Low et al72 compared the effects of EACA and TXA on

postoperative cognitive dysfunction (POCD) after a variety of cardiac surgeries all involving CPB, by

retrospectively using 151 control-arm patients from a previous study. Sixty-nine patients received TXA,

86 received EACA, and propensity matching adjustment was performed due to significant variation in

total CPB duration. Their multivariate analysis demonstrated higher rates of POCD at six weeks in the

EACA group (59.3%) versus TXA (46.4%) (odds ratio (OR) 3.28; 95% CI, 1.49 - 7.62, p=0.005). This trial is

the first to examine the relation between POCD and antifibrinolytics.72

Renal injury has been linked to EACAs association with increases in the excretion of 2-

microglobulin (a protein injurious to the renal tubular system) as well as thrombus-induced ureteral

obstruction, microscopic angiopathy leading to renal infarction, and myoglobinuria.73-75 EACAs exact

contribution to postoperative AKI is conflicting. In cardiac surgery, a single center observational trial of

120 patients comparing EACA and TXA found no postoperative AKI differences between the two

agents.32 A 2011 Cochrane review involving a mix of cardiac and non-cardiac surgery trials found no

increases in EACA-associated AKI when either compared against placebo or compared to TXA

corroborating the findings of more contemporary studies.28, 32, 76 A 2012 systematic review combined

randomized and observational trials to specifically examine antifibrinolytic safety in cardiac surgery.

From a postoperative AKI perspective, the authors found EACA use to be the safest strategy as

compared to placebo, TXA, or aprotinin.77 In contrast, a prospective comparison of EACA and TXA used

in 64 patient undergoing thoracic aorta surgery found greater AKI rates in the EACA group (EACA 40% vs

12
TXA 16%, p=0.04).31 A recent retrospective study comparing EACA versus placebo in OLT found no

increased rates of postoperative AKI at one week but there was an increased need for renal replacement

therapy within the first postoperative month (19% vs 11%, p=0.0026).78

EACA-induced rhabdomyolysis and myopathy have been reported in a number of case reports,

particularly when used chronically in the outpatient setting for various bleeding diastheses.79-82

Perioperative hyperkalemia secondary to EACA administration has been described in two case reports.83,
84
One case occurred during CABG surgery; higher than typical doses of EACA were administered (10 g

bolus, followed by 10 g doses at 60 and 120 minutes), serum potassium peaked at 6.7 mmol/L at 140

minutes, was successfully treated with insulin and furosemide, and was not associated with EKG or

hemodynamic changes. The second case occurred in a patient with chronic kidney disease undergoing

revision THA who received a 10 g bolus followed by an intraoperative infusion of 1.0 g/hr; serum

potassium peaked at 6.9 mmol/L, was successfully treated intraoperatively, and also had no EKG

changes or hemodynamic instability. The etiology of this is likely due to the structural similarity

between EACA and lysine by which cationic molecules cause potassium flux from the intracellular to the

extracellular space in order to maintain electroneutrality. This hyperkalemic risk is increased in the

context of concomitant renal insufficiency.84

As previously mentioned, EACA must be used cautiously in the context of traumatic brain injury

or aSAH due to the risk of cerebral sinus thrombosis. Additionally, a 2015 trial in aSAH where patients

received EACA and were screened for DVT demonstrated that even a short course (< 48 hours) of EACA

was significantly associated with DVT formation (OR 8.49; 95% CI, 1.27 - 77.1).85 EACA is contraindicated

when there is evidence of an active intravascular clotting process such as DIC. It is important to

distinguish between primary fibrinolysis and DIC prior to administering EACA. This can be done by

performing a protamine paracoagulation test (positive in DIC), the euglobulin clot lysis test (normal in

DIC), and evaluating the platelet count (usually decreased in DIC). Thromboembolic sequelae should be

13
of concern when using any procoagulant; however, there is no definitive evidence that EACA (or TXA)

used in conjunction with either rFVIIa or activated prothrombin complex concentrates for significant

hemorrhage is associated with increased thrombotic complications. To the contrary, there are reports

of successfully managing life-threatening bleeding without thrombosis development by the use and co-

administration of high-dose EACA with rFVIIa.86, 87

The benzyl alcohol preservative used in IV formulations of EACA has been associated with a

potentially lethal syndrome in low-birth weight infants and neonates known as gasping syndrome. In

1982 there were 16 reported neonatal deaths thought to be caused by benzyl alcohol poisoning from

various IV solutions which led to an alert on any IV solution containing benzyl alcohol.88 There is no data

or case report specifically implicating EACA but there is a theoretical risk with its use. This syndrome is

so named due to a gasping ventilation pattern secondary to increased serum levels of benzyl alcohol and

its metabolites. Other features of gasping syndrome include, central nervous system depression,

metabolic acidosis, hypotension, intracranial bleeding, hepatic failure, renal failure, bradycardia, and

cardiovascular instability.89 Other relative contraindications include benzyl alcohol hypersensitivity,

paraben hypersensitivity (used in oral preparation), pregnancy, and breast-feeding.20, 89

Tranexamic Acid

Similar to EACA, TXA (trans-4-aminomethylcyclohexane-1-carboxylic acid; Cyklokapron,

Pharmacia & Upjohn Company LLC, Kalamazoo, MI) is also a synthetic lysine derivative, which

competitively blocks the lysine-binding site on plasminogen thereby inhibiting fibrinolysis.90 See Figure

2. TXA was originally discovered by Japanese physician and researcher Utako Okamato in the 1950s.

Okamato and her group first published the findings regarding their novel drug in 1962 and the original

applications of TXA were in the management of postpartum hemorrhage and hemophilia.91, 92 It was not

until the 1990s that the use of TXA use was applied in cardiac surgery.93, 94

14
Tranexamic acid mechanism, pharmacokinetics, and dosing

TXA has a strong affinity for the lysine binding sites on the TPA and plasminogen molecules and

reversibly blocks them achieving antifibrinolysis.95-97 Plasminogen has several lysine binding sites and it

is thought that there is one high affinity and four to five lower affinity lysine binding sites.96 TXA exerts

its effects primarily by blocking the high affinity site.90 See Figure 2.

The pharmacokinetic properties of TXA vary depending on route of administration and

comorbidities such as renal insufficiency. TXA can be administered IV, intramuscular, topically, and

orally. The administration of 10 mg/kg IV bolus generates a plasma concentration of 10 mg/L.98 Plasma

levels of 10 mg/L have been reported to inhibit only 80% of TPA activity while a ten-fold higher dose

(100 mg/L) is needed for 100% inhibition.99, 100 In cardiac surgery, there are a number of trials examining

TXA dose-response relations along with its pharmacokinetics. Horrow et al101, without an examination

of plasma TXA levels, showed that a lower-dose regimen (10 mg/kg bolus + 1 mg/kg/h infusion)

effectively minimized blood loss while higher doses (20-40 mg/kg bolus + 2-4 mg/kg/h infusion) had no

additional benefit. Follow-up trials seeking to possibly find lower optimal doses were inconsistent in

demonstrating adequate plasma levels to achieve the goal of 100% inhibition of TPA activity.102, 103

Sharma et al100, using the same dosing from the BART trial (see Table 1), achieved plasma TXA

concentrations between 100 150 mg/L throughout the intraoperative period with mean plasma TXA

concentrations at six hours postoperatively of > 10 mg/L. Nonetheless, it is still unknown the precise

effective TXA dose that inhibits in-vivo fibrinolysis with no consensus on a single optimal dosing regimen

in cardiac surgery.100

TXA has nearly no plasma protein binding and is metabolized to a very small extent with the

highest levels noted in liver, kidney, and lungs.90 TXA crosses the placenta and can be found in fetal

blood in the concentrations similar to those in maternal blood but the concentration in breast milk

appears to be one hundredth that of plasma with no adverse long-term effects to exposed breastfeeding

15
infants.98, 104 Administration of a single IV dose of 1 gram leads to 95% of unchanged drug in the urine in

24 hours and up to 99% in 72 hours.90, 98 Using a two-compartment model, TXA undergoes first-order

elimination kinetics via glomerular filtration, therefore appropriate dosage adjustments should be made

in the patients with impaired creatinine clearance.90, 98, 100, 105 See Table 1 for renal dosing

recommendation.

Tranexamic acid use in cardiac surgery

TXA became one of the key components of antifibrinolytic therapy after it was found to be safer

than other agents in the BART trial.28 A 2011 systematic review and meta-analysis of 8 studies, which

included 544 patients, found TXA to significantly reduce the requirement for blood transfusion (RR 0.47;

95% CI, 0.33 - 0.66, p<0.0001).106 This was corroborated in 2012 by Ker et al107 who also published a

systematic review and meta-analysis of effects of TXA on surgical bleeding which included evidence over

several decades, specifically looking at the quantity of blood transfused in cardiac surgery. In 42

identified studies they found TXA highly efficacious in reducing the risk of transfusion (RR 0.65; 95% CI,

0.60 - 0.70, p<0.001).107 Myles et al108 published a recent prospective trial examining TXA use in a

variety of cardiac surgeries (CABG, OPCAB, combined CABG-valve replacement). Though the primary

outcome was powered to examine potential adverse thromboembolic events associated with TXA,

certain secondary outcomes are noteworthy. Secondary outcome findings included 4,331 total units of

blood products transfused during the hospital course in the TXA group versus 7,994 in the placebo group

(p<0.001). Major hemorrhage or cardiac tamponade that required a return to the operating room

occurred in 1.4% of the TXA group versus 2.8% in the placebo group (RR 0.49; 95% CI, 0.32 - 0.75,

p=0.001). Moreover, as compared to placebo, those in the TXA arm had lower rates for the following

bleeding-related secondary outcomes: units of red cells transfused during hospitalization (p<0.001) and

transfusion of any blood product during hospitalization (p<0.001). Those in the TXA group were

transfused 46% fewer units of blood products than the placebo arm. The authors extrapolated that in a

16
similar cardiac surgical practice, the use of TXA would save nearly 57 units of blood products for every

100 patients treated.108

Tranexamic acid - use in off-pump coronary artery bypass surgery

The beneficial effect of TXA has been specifically investigated in OPCAB surgery, with a number

of initial small studies demonstrating a reduction in perioperative bleeding compared to placebo

without observing an increase in thrombotic complications.109-115 The hemostatic benefit of TXA in

OPCAB was later corroborated in the largest RCT to date by Wang et al.116 In this trial of 231 consecutive

patients (TXA = 116, placebo = 115) undergoing OPCAB, the authors quantified postoperative chest tube

output for a 24-hour period as the primary endpoint. Some of the noteworthy secondary endpoints

included six-hour postoperative chest tube drainage, blood product utilization (intra- and

postoperative), in-hospital all-cause mortality, stroke, and acute myocardial infarction. In this trial, the

authors reported a significant reduction in blood loss at 6 hours (TXA, 270 118 mL vs control, 416 179

mL, p<0.001) and 24 hours (TXA, 654 224 mL vs control, 891 295 mL, p<0.001) in the TXA treated

group compared to placebo, corresponding to a reduction in allogeneic red blood cell (47% vs 31.9%,

p=0.019) and fresh frozen plasma (29.6% vs 17.2%, p=0.027) transfusions, respectively. Moreover, there

were no differences with respect to mortality, morbidity, thromboembolic rates, and resource utilization

between the TXA and placebo groups. The collective results of the aforementioned studies have

provided the data to support the safe use of TXA in patients undergoing OPCAB (level of evidence A).109-
117
In addition to a reduction in blood loss and blood transfusion requirement, it is important to

highlight that TXA has not been shown to increase thromboembolic complications during OPCAB.109-117

Tranexamic acid - non-cardiac surgery

Trauma

It is estimated that 400,000 people worldwide die each year from traumatic bleeding.118 In

2010, the largest prospective clinical trial to date, Clinical Randomization of an Antifibrinolytic in

17
Significant Hemorrhage-2 (CRASH-2) was published. This landmark study included a total of 20,211

(10,096 TXA and 10,115 placebo) adult trauma patients in 274 hospitals in 40 countries and evaluated

the effect of early administration of TXA on death, vascular occlusive disease, and receipt of blood

transfusion. Mortality was significantly reduced in the TXA group versus placebo group (RR 0.91; 95% CI,

0.85 - 0.97, p=0.0035) and additionally the risk of death due to bleeding was significantly reduced (RR

0.85; 95% CI, 0.76 - 0.96, p=0.0077).119 The timing of TXA administration in CRASH-2 is important to

highlight. TXA benefits were only seen when administered within three hours of presentation. When

given after three hours there was an increase in mortality due to bleeding (RR 1.44; 95% CI 1.12 1.84,

p=0.004). Following CRASH-2 publication, two large military retrospective studies were undertaken to

look at the effect of TXA on mortality.

These were the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation

(MATTERs) study in 2011 and MATTERs II study in 2013. The first MATTERs study included a total of 896

patients with combat injuries, of whom 293 received TXA. The overall mortality was lower by 6.5%

(p<0.03) in the TXA group (17.4%) vs no-TXA group (23.9%). The authors did note that patients in TXA

group had more severe injuries based on the Injury Severity Score and that patients in the TXA group

received significant amounts of cryoprecipitate in addition to blood as well.120 The TXA benefit

appeared to be greatest in patients who received massive transfusion (defined as the need for 10 or >

units of red cells in 24-hours) and it was found to be independently associated with survival (OR 7.228;

95% CI, 3.106 - 17.322, p<0.001).120 The purpose of the MATTERs-II study was to evaluate the effect on

mortality of cryoprecipitate alone or administered with TXA. MATTERs-II included a total of 1,332

patients spilt into four groups: TXA (n=148), cryoprecipitate (n=168), TXA/cryoprecipitate (n=258), and

no TXA/cryoprecipitate (n=758). The lowest mortality was in TXA/cryoprecipitate group (11.6%)

followed by TXA group (18.2%), compared with cryoprecipitate group (21.4%) and no

TXA/cryoprecipitate (23.6%).121 The authors concluded that cryoprecipitate may add to survival in

18
severe trauma requiring transfusion. TXA had an independent survival odds ratio of 0.61 (95% CI, 0.42 -

0.89, p=0.01), cryoprecipitate had independent survival odds ratio of 0.61 (95% CI, 0.40 - 0.94, p=0.01),

and combination of TXA and cryoprecipitate group had independent survival of 0.34 (95% CI, 0.20 - 0.58,

p<0.001).121

Orthopedics

The use of TXA in orthopedic surgery has been studied extensively, particularly in procedures

with a high potential for blood loss such as THA and TKA. Wei et al122 conducted a meta-analysis of

2,720 THA and TKA cases and found that TXA significantly reduced blood loss and the need for blood

transfusion. The number of patients receiving at least one unit of red blood cells was decreased in the

TXA group vs control group, (RR 0.50; 95% CI, 0.35 - 0.65) in THA patients and (RR 0.53; 95% CI, 0.45 -

0.63) in TKA patients.122 These findings are supported in another meta-analysis of 28 RCTs selected for

patients undergoing TKA showing significant reduction in blood loss by 420 mL (95% CI, 327 - 514) in

patients who received TXA.123 Similar results were seen in a third meta-analysis of 770 patients

undergoing hip fracture surgery managed by variety of surgical techniques. TXA administration was

associated with a 46% risk reduction in requirement for blood transfusion irrespective of the type of hip

surgery (RR 0.54; 95% CI, 0.35 - 0.85, p<0.0001).124 In spine surgery, a 2013 meta-analysis of six placebo-

controlled RCTs demonstrated TXAs effectiveness in reducing total intraoperative blood loss (mean

difference (MD) = 285 mL; 95% CI, 507 - 64, p=0.01) and transfusion rates (RR = 0.71; 95% CI, 0.54

0.92, p=0.01).125 A second 2015 meta-analysis of 11 RCTs in spine surgery, which included total of 644

patients, found that TXA reduced intraoperative blood loss by 219 mL (95% CI, -116 - -322ml, p<0.05)

and total blood loss by 202 mL (95% CI, -105 - -299, p<0.05).126

Subarachnoid hemorrhage

Similar to EACA, a short course use of TXA should be considered to prevent rebleeding after

aSAH.53-55 Currently the Dutch ULTRA trial (Ultra-early tranexamic acid after subarachnoid hemorrhage

19
trial), initiated in 2013 with expected completion in 2019, is examining whether ultra-early and short-

term administration of the TXA (1 g TXA bolus as soon as possible after randomization followed by 1 g /

per-8 hour infusion to maximum of 24 hours), in addition to standard aSAH management, leads to

better functional outcome.56 The ULTRA trial is also utilizing lower TXA doses as a means to possibly

help obviate delayed cerebral ischemia risk.51

Obstetrics

One of the original uses for TXA was to treat PPH. The drugs efficacy in this indication is unclear

and a recent analysis of 26 trials was unable to find conclusive evidence due to poor trial design and

variations in randomization.127 However, there may soon be an improved understanding of TXA use in

PPH. The World Maternal Antifibrinolytic Trial (The WOMAN trial) is currently underway and recruiting

20,000 patients in 21 countries to evaluate early administration of TXA on mortality in women with

PPH.128 As of the writing of this article, full recruit numbers have been achieved and trial is being

analyzed.129

Topical use of tranexamic acid

Topical use of TXA has been of increased interest in recent years, particularly in orthopedic

surgery. TXA solution is applied to the surgical field, rather than being administered IV with the goal of

decreasing systemic side effects. In a recent multicenter RCT of 150 patients undergoing TKA, patients

were separated into 3 groups (no TXA, IV TXA, topical TXA). No significant difference was seen in blood

loss or adverse events when comparing IV versus topical TXA.130 The authors of this trial also pointed

out that there is no consensus on how to best administer topical TXA, with various techniques employed

including spraying the joint after the arthroplasty, injecting TXA through the drain tube, injecting the

medication into the joint after closure, and bathing the joint before wound closure.130 A meta-analysis

of 2056 patients undergoing THA also demonstrated no significant difference between topical and IV

administration of TXA with regards to transfusion requirement or total blood loss.131 In contrast, a 2016

20
trial with 139 patients randomized to topical versus IV TXA demonstrated a significant decrease in blood

loss in the IV group versus topical (1190 mL vs 1443 mL respectively, p=0.006).132 It is still unclear

whether there is a true advantage in using topical TXA with mixed findings possibly related to non-

standardized methods of applying topical TXA as well as variability in dosing.

Tranexamic acid safety and precautions

As previously described, TXA excretion is dependent on renal function and excretion decreases

with increasing levels of plasma creatinine.133 Therefore, caution should be used in administration to

patients with renal impairment and dose adjustment should be made.90 There is limited TXA

pharmacokinetic data in patients with renal dysfunction undergoing cardiac surgery. Fiechtner et al102,

using data only from four patients, was one of the first groups to examine TXA pharmacokinetics during

CPB in order to generate a dosing regimen in the context of renal dysfunction. In 2015, Yang et al133

using previously published TXA pharmacokinetic data from 15 patients and a two-compartment

simulation model, developed a dosing regimen in chronic renal dysfunction based on achieving a plasma

TXA concentration of 100 mg/L. See Table 1.

The use of TXA in non-cardiac surgery has increased in recent years partly due to the fact that

most of the retrospective analyses have shown TXA to be relatively safe with regards to

thromboembolic events.122 However, other than the recent trial by Myles et al108 (see below) that

demonstrated TXA does not increase thromboembolic risks in the cardiac surgery context, there have

been no RCTs conducted and designed to specifically evaluate TXA and its relation to thromboembolic

events in non-cardiac surgery.134 Analogous to cardiac surgery, virtually all TXA trials to date in non-

cardiac surgery have focused on mortality benefits and blood loss reduction. A recent retrospective

cohort study conducted using the Michigan Arthroplasty Registry analyzed 23,236 TKAs (11,143 with

TXA) and 11,489 THAs (5,864 with TXA) found no increases in venous thromboembolism (VTE) rates

within 90 days of surgery or cardiovascular complications within seven days of surgery in both THA and

21
TKA.135 In the trauma setting of CRASH-2, there also was no difference in thrombotic events in those

receiving TXA (RR 0.84; 95% CI, 0.68 - 1.02, p=0.084).119

Although no large trials have shown an increased risk for thromboembolic events, there are

multiple case reports of these events in the literature including cerebrovascular accident, PE,

intracardiac thrombosis, and DVT, particularly with higher doses of TXA.134, 136-139 There is limited

evidence that it may be a better option to use topical TXA when possible in patients with increased

thrombotic risk.140 Caution should be used in patients with prior thromboembolic events, those with

inherited and acquired hypercoagulable states, or patients receiving other prothrombotic

medications.10, 90, 134, 141 TXA is associated with seizures (see following section), therefore patients with a

preexisting or poorly controlled seizure disorder may be poor candidates for TXA.142 See Table 2 for a

listing of precautions.

In October 2016, Myles et al108 published the first trial prospectively examining the

thromboembolic risks of TXA in on- and off-pump CABG surgery. Between 2006-2015, 4,662 patients

were enrolled (after 29 exclusions, 2,311 received TXA (758 at 100 mg/kg, 1,553 at 50 mg/kg) vs 2,322

placebo) with a primary outcome of a composite of death and thromboembolic complications (nonfatal

myocardial infarction (MI), stroke, pulmonary embolism (PE), renal failure, or bowel infarction) within 30

days after surgery. The primary outcome occurred in 16.7% (n=386) of the TXA group versus 18.1%

(n=420) in the placebo group (RR 0.92; 95% CI, 0.81 - 1.05, p=0.22). Subgroup analysis for the primary

outcome did not demonstrate any significant interactions. Hence, there was no evidence demonstrating

that TXA use led to any increased risk of a thromboembolic complications or death in the context of

CABG surgery.108

TXA-related thromboembolic risk in the non-cardiac surgery context still needs investigation.

Although the large studies conducted to date have not demonstrated an increased risk of developing

thromboembolic events, there are multiple case reports of patients suffering adverse events with

22
administration of TXA. It is therefore important to weigh risk versus benefit and consider relative

contraindications to the administration of TXA.

Tranexamic acid-associated seizures

Tranexamic acid (and to a much lesser extent, EACA143) associated seizures have been well

documented and observed in a variety of patients. Most commonly they occur in patients after cardiac

surgery. There have also been multiple case reports citing postoperative seizures in patients who

received TXA and had no prior seizure history.143, 144 The mechanism of TXA associated seizures is not

completely understood. TXA has been shown to enter the central nervous system (CNS) and it is

postulated to behave as a disinhibiting molecule by affecting GABA-A and glycine receptors which are

major CNS inhibitors and frequent targets of anticonvulsive therapy.143 A large meta-analysis conducted

by Lin et al145, which included 26,079 patients in the TXA exposure group and 7,395 patients in the non-

TXA exposure group who underwent cardiac surgery or pulmonary endarterectomy, reported an overall

seizure incidence of 2.7% (95% CI, 2.0 - 3.3, p<0.001). The authors found that the odds ratio of seizure in

the TXA exposure group vs the non-TXA exposure group was 3.91 (95% CI, 2.22 - 3.91, p<0.001). A study

conducted by Martin et al144, which included a total of 1,188 cardiac surgery patients (TXA: n=592 and

aprotinin: n=596), found that 27 patients (4.6%) in the TXA group versus 7 patients (1.2%) in the

aprotinin group sustained seizure activity (p<0.001).

Two variables that appear to play a role in the likelihood of developing TXA-associated seizure

are dosage and cardiac surgery.146 Firstly, it has been postulated the seizure rate is higher in cardiac

versus non-cardiac surgery due to cerebral emboli engendered blood-brain barrier disruption as well as

the relatively higher total doses administered in cardiac versus non-cardiac surgery.146, 147 With regard

to dosage, a study of 8,929 patients who underwent CPB, a dose of TXA > 100 mg/kg was found to be an

independent predictor of generalized tonic-clonic seizures within 24 hours of surgery with an adjusted

OR 2.6 (95% CI, 1.7 - 3.8, p<0.001).148 Similar findings were seen in the meta-analysis described above

23
by Lin et al145 which showed the high dose TXA group had a seizure rate of 5.3% versus middle dose rate

of 2.4% and a low dose rate of 1.4%. If a dose adjustment is not made in those with renal dysfunction,

TXA plasma levels will be predictably higher than in a normal population, leading to a potentially

increased seizure risk.145 Two recent trials stand in contradistinction to this dose effect. Siguat et al149

comparing low dose (n=284; 10 mg/kg bolus, 1 mg/kg/h infusion) and high dose (n=285; 30 mg/kg bolus,

16 mg/kg/h infusion) regimens in cardiac surgery found no difference in postoperative seizure rates

between their two groups either at one week (2 low dose vs 4 high dose, p=0.7) or at 28 days (3 low

dose vs 5 high dose, p=0.8). The recent trial by Myles et al108, which used a relatively higher TXA dose

(50-100 mg/kg) also contradicts a dosage effect. Though their trial corroborates the association of

seizures with TXA (0.7% in TXA arm vs 0.1% in placebo arm (p=0.002 by Fishers exact test)), it is unclear

as to why their TXA-associated seizure rate was lower than that reported in prior studies even though a

considerably higher TXA was used dose in their intervention arm. In personal communication with the

lead author (P. Myles), the possibilities that the use of propofol sedation postoperatively and a lower

percent of open-chamber procedures (a reported seizure risk factor147) contributed to their overall

lower seizure rate.

Aprotinin

Aprotinin (Trasylol, Nordic Group, Paris, France) is a naturally occurring single chain 58 amino

acid polypeptide originally extracted from bovine tissue and is currently produced using recombinant

technology.50, 150, 151 Categorized as a nonspecific Kunitz-type serine protease inhibitor, its

antifibrinolytic effects are mediated via potent direct non-competitive inhibition of plasmin but it is also

an inhibitor of trypsin, chymotrypsin, both tissue and plasma kallikrein factor XII, and platelet protease-

activated receptor-1.50, 151-153 Kunitz domains are the active binding sites on proteins which inhibit a

given enzymes protease function.154

24
Aprotinin - history and development

Initially described in the 1930s, aprotinin was first used in the clinical setting in the 1950s for

treatment of hyperfibrinolytic conditions such as pancreatitis.155 The prohemostatic properties of

aprotinin were a serendipitous discovery by Kirkland et al in the early 1980s, who noted an unusually

dry cardiac surgical field following CPB when using aprotinin to attenuate the CPB-associated

inflammatory response and post-perfusion syndrome.156 Subsequent studies focused on its effect on

coagulation with a landmark paper finding significantly reduced blood loss and need for transfusion with

aprotinin in repeat cardiac surgery.157 Aprotinin received FDA approval in 1993 for use in routine CABG

surgery.

Aprotinin mechanism of action and pharmacokinetics

See Figure 1 for aprotinin structure and Figure 2 for mechanism of action. Aprotinin and other

serine protease inhibitors inactivate free plasmin but have little effect on bound plasmin.151 Moreover,

plasma kallikrein and activated Factor XII are generated by the inner surface of the negatively-charged

CPB circuit (both proteins accentuate CPB coagulation changes); aprotinins kallikrein inhibition helps to

attenuate this derangement.158 It is metabolized by lysosomal enzymes and is renally excreted with an

elimination half-life of 5 - 10 hours. Aprotinin works as an enzyme inhibitor and the reduction in

bleeding and transfusion requirement following surgery follows a dose-response curve borne out of

RCTs in cardiac, major orthopedic,159 and liver transplant surgery.9

Aprotinin - market withdrawal in United States and current use

While aprotinin had demonstrable efficacy in the decade following its 1993 market approval, its

safety profile came into question in the mid-2000s.160 Various reports implicated aprotinin with multiple

adverse events including increased renal dysfunction and five-year mortality.25, 161 Aprotinin safety

concerns were raised in 2006 by Mangano et al25 in their large prospective cohort study of 4,374

patients undergoing CABG in which aprotinin, EACA, TXA, and a control were all compared. They found

25
aprotinin, unlike TXA and EACA, to be associated with an increased risk of renal failure, encephalopathy,

MI, stroke, and mortality. Though EACA and TXA were not associated with these increased risks, the

reduction in blood loss was found to be similar for all three drugs.25 In the same year Karkouti et al161

reported similar findings related to aprotinin use in cardiac surgery. The FDA, in 2006, added renal

dysfunction to aprotinins safety issues along with anaphylaxis, graft occlusion, and stroke.155 In 2007,

Furney et al contested the possible link between aprotinin and renal dysfunction in a prospective

observational study examining 11,198 cardiac surgery patients in which 25% received aprotinin.162 They

concluded that red cell transfusion was a major confounding variable and that renal dysfunction was not

associated with aprotinin use when risk adjustment for the number of transfused red cell units was

factored into the overall analysis. However, also in 2007, Mangano et al published a new analysis using

their 2006 data related to aprotinin safety and concluded that its use was independently predictive of 5-

year mortality.163

To address these safety concerns further, the previously discussed BART trial was conducted.28

In October 2007, the trial was terminated prior to target enrollment due to an increase in all-cause

mortality in the aprotinin group, with the investigators concluding that though the possibility of a

modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend

associated with aprotinin, as compared to the lysine analogues, precludes its use in high-risk cardiac

surgery. Results from the BART trial as well as an FDA warning led to the withdrawal of aprotinin from

the US in late 2007 followed by regulatory agencies suspending the drug license in Canada and Europe in

2008.155 Current STS/SCA guidelines on blood conservation now give aprotinin a Class IIIA

recommendation against its routine use with an explicit statement regarding its association with

increased renal injury and mortality rates.1 Subsequent to BART, evidence emerged that the worldwide

suspension of aprotinin may have been premature and reactionary. In one single-center observational

trial comparing outcomes before and after the aprotinin prohibition (aprotinin: n=325 versus lysine

26
analogues: n=456), avoidance of aprotinin did not translate to a decrease in mortality with a

comparatively greater blood product usage with the lysine analogues.164 The BART trial was

subsequently critiqued by Canadas health regulatory body (Health Canada) which made the

determination that the sweeping withdrawal of aprotinin had been inappropriate based on all the

available data. Criticisms of BART methodology included: off-label use of aprotinin, bias due to financial

support from drug companies, unexplained exclusion of large sets of patients which would have

changed outcome data (137 excluded patients from the intention-to-treat analysis), disparities in the

use of heparin use, inappropriate monitoring of anticoagulant use, and improper design to examine

mortality relative to the lysine analogues.165-167 Based upon these analyses, the recommendation was

made by the Health Canada in 2011 to permit aprotinin use in adults undergoing isolated CABG and

similarly in 2012 by the European Medicines Agency to also lift its suspension.168-170 Aprotinin is

currently available in Canada, the United Kingdom, Sweden, and the Netherlands, with ongoing

negotiations in other European countries. Its use is now subject to strict monitoring under the Nordic

Aprotinin Patient Registry.168-171 Information provided by personal communication with Nordic Pharmas

medical affairs international clinical project manager indicates that the registry and safety data on

aprotinins current use would be ongoing for the next three years with no data published until that time.

In 2014, the BART trial authors published a set of responses to what they deemed the most

important trial criticisms that led to the re-release of aprotinin in Canada and parts of Europe. The

details of each of the counter-arguments is beyond the scope of this review. However, the authors

explain that a more prudent regulatory action would be the conduct of a second large trial to compare

aprotinin against the lysine analogues in order to clarify the original BART findings as well as articulating

that the current, albeit limited, availability of aprotinin may not be justified and may be dangerous.172

27
Aprotinin safety and precautions

The only absolute contraindication to aprotinin is a positive aprotinin-specific IgG antibody test

prior to use. Guidelines do not exist however regarding application of this test. Contingencies must be

in place for anaphylaxis or anaphylactoid reactions whenever the drug is used and special care should be

taken for patients who have received aprotinin in the last 12 months.155, 173 Aprotinin may also falsely

elevate or prolong various in-vitro clotting indices including partial thromboplastin time and activated

clotting time measurements. For this reason, monitoring of anticoagulation with a minimal celite ACT of

750 seconds or kaolin-ACT of 480 seconds is recommended.155

Aprotinin is a potent inhibitor of fibrinolysis and is efficacious in decreasing transfusion

requirements in cardiac surgery; however, its safety profile remains an issue of controversy amongst

experts worldwide. Future directions for aprotinin may include the study of its application beyond the

current approved indication in on-pump CABG surgery; indeed there is data to support its major utility in

more complex, higher risk cardiac operations.174, 175 While not exempt from possible bias, data gleaned

from Nordic Groups safety registry may assist in better appreciating aprotinins safety issues.

Antifibrinolytic agents for pediatric patients

Once relegated almost entirely to the realm of cardiac surgery, antifibrinolytics have now found

a use in almost every category of pediatric surgical subspecialties where significant blood loss is a

possibility. The bulk of antifibrinolytic drug doses are still administered to cardiac surgical patients. One

survey of 36 tertiary care childrens facilities demonstrated that 64% of patients who received TXA

between 2009 and 2013 were cardiac surgical patients. Pediatric trauma patients only accounted for

0.31% of patients while the remaining balance was made up of pediatric patients who received surgeries

for scoliosis (18%), craniosynostosis and other craniofacial defects (3.6%), and 14% of patients were

lumped into an other category.176

28
Pediatric cardiac surgery

TXA and EACA are the two agents used most commonly in pediatric cardiac surgery. There is

data to suggest, though, that complications of aprotinin such as increased mortality and renal failure

that occur in adults may not occur in the pediatric population.177, 178 Aprotinins superior efficacy over

the lysine analogues is still controversial with one retrospective study exhibiting aprotinins ability to

reduce blood product use as well as attenuating cytokine activation compared to TXA.179 However,

other data including a meta-analysis study found that TXA was not less effective in reducing blood loss

when compared to aprotinin.180 Curiously, a historical comparative investigation of the use of rFVIIa

(before and after the ban on aprotinin), in one congenital cardiac center, found an increased use of

rFVIIa after the ban was implemented as well as an increase in the incidence of surgical re-exploration

following the withdrawal on aprotinin.181

Even though the use of antifibrinolytics is widespread amongst congenital cardiac programs

across the world, the evidence for its superiority over placebo for improving actual outcomes is still not

as robust as one might expect. One prospective single-blinded, randomized trial found that patients

who received TXA had significantly less blood loss at the first 24-hours compared to a group that

received placebo. But, there was no statistically significant difference in the amount of blood transfused

in each group. There was also no difference in the duration of mechanical ventilation and intensive care

unit stay.182 A retrospective analysis of data at one congenital cardiac surgery center in Naples, Italy did

show a significant decrease in the amount of blood transfused in the group of patients that received

TXA.183 Additionally, a recent meta-analysis of RCTs also suggested benefits, indicating that patients

who received EACA were transfused statistically significant lesser amounts of fresh frozen plasma and

platelet concentrate compared to patients who did not receive EACA. The patients who received EACA

also had a significantly lower re-exploration rate.184

29
 There does not appear to be a demonstrable advantage of TXA over EACA. A prospective

observational study by Martin et al185 determined that there was no difference in blood loss over the

first 24 hours, rates of reoperation or amounts of blood products transfused between pediatric cardiac

surgical patients that received TXA versus EACA. There was a fourfold, although not statistically

significant, increase in the incidence of seizures in those patients that were given TXA.185 A previous

retrospective comparison of aprotinin and TXA from the same research group also found a similar, but

not significant incidence of seizures (3.5% vs 0%) in the group of patients who received TXA.186 Clinicians

should take this into consideration when choosing between TXA and EACA given the higher incidence of

postoperative seizures in the neonatal population following cardiac surgery. In one study it was as high

as 8% (13 of 161 patients).187 Worrisome is the fact that most of the seizures were found only by

electroencephalogram (85% of the 13 patients) and additionally status epilepticus occurred in the

majority of these patients (62% of the 13 patients). Seizures were a sign of greater illness severity and

higher mortality.187 Seizures are also associated with lower developmental scores on executive function

tasks such as inhibition, planning and mental flexibility at four years of age.188

One must exercise caution when using these drugs when a cyanotic patient has a modified

Blalock-Taussig-Thomas (BTT) shunt or a patient is undergoing a surgery involving reimplantation of

coronary arteries. Use of these agents can theoretically increase the propensity to cause thrombosis in

these critical flow conduits. Anecdotally, these authors have witnessed thrombosis of a BTT shunt

following the initial dose of EACA in a patient undergoing a bidirectional Glenn procedure. This might be

related to the increased platelet activation and diminished anticoagulant activity seen in the

endothelium of cyanotic patients.189 In Glenn shunts, Ravn et al190 describe not just increased platelet

aggregation but also describe a reductions in protein C, protein S, and antithrombin III. The composite

of these issues contributes to an increased thrombosis potential.190

30
Pediatrics - scoliosis surgery

The use of TXA and EACA has gained wide popularity in the field of posterior spinal fusion

surgeries for scoliosis. Several studies have demonstrated diminished blood product usage when an

antifibrinolytic agent is used compared to placebo. It must be noted that these surgeries tend to be

performed on an older cohort of patients usually in their adolescence but some patients with

neuromuscular scoliosis (NMS) may have surgery around three years of age. A study conducted at

Cincinnati Childrens Hospital demonstrated significantly lower mean intraoperative blood loss in

patients who received TXA during scoliosis surgery.191 A separate multicenter retrospective study

corroborated the same findings demonstrating that TXA and aprotinin both led to significantly less blood

loss as compared to patients who did not receive antifibrinolytics.192 A conflicting multicenter

retrospective study was not so definitive.193 Intriguingly it found that only EACA in adolescent idiopathic

scoliosis patients significantly reduced the odds of transfusion. TXA did not have a significant effect of

lowering transfusion in adolescent scoliosis patients and neither EACA nor TXA lowered the need for

transfusion in patients with NMS.193 A large multicenter trial is needed in order to clarify the benefits

and risks. The dosing regimens for TXA and EACA for spinal column surgery vary greatly by center and

seemingly one drug is not necessarily more popular than the other. See Table 1 for further pediatric-

related dosing.

Pediatrics - craniofacial and craniosynostosis surgery

There exists wide agreement amongst most studies that this particular category of patients

benefits from the use of antifibrinolytics. This may stem from the fact that the majority of these

surgeries are performed during infancy to early childhood. A well conducted double-blind, placebo-

controlled trial published in 2011 by Goobie et al194 concluded that TXA is effective in reducing

perioperative blood loss craniosynostosis procedures. They found significant reductions in mean blood

loss and mean blood transfusions. Several recently published retrospective articles have espoused

31
similar findings. The same research consortium of Goobie et al published a retrospective chart review

which concluded that TXA use was significantly associated with fewer post-operative adverse events

requiring ICU admission.195 Crantford et al196 found that TXA use during cranial vault reconstruction

significantly reduced perioperative blood loss and transfusions. Furthermore, a 2016 retrospective trial

found EACA to be efficacious in reducing blood loss and the need for transfusions.197 It is still unclear if

the amount of blood loss reduction offered by these drugs actually leads to a change in outcome.

Martin et al198 conducted a retrospective study which substantiated all of the findings of the previously

mentioned studies but those not treated with TXA had similar postoperative hematocrits to those

treated with TXA. Also, those not treated with TXA had no higher incidence of postoperative

complications or mortality.198

The most recently published meta-analyses on this subject are somewhat split in their results.

Song et al199 did not find that TXA significantly reduced blood loss when analyzing RCTs published from

1966 to 2012. On the other hand, Basta et al200 included TXA, EACA, and aprotinin in their meta-analysis

of studies from 1990 to 2012 and found that the use of these agents significantly reduced perioperative

blood loss and total transfusion volume. On balance, the evidence for use in this population of patients

is compelling.

Pediatric trauma surgery

There is a paucity of data regarding antifibrinolytic use in the pediatric trauma population.

CRASH-2 demonstrated the effectiveness of TXA as an important adjuvant drug to reduce mortality in

unstable adult trauma patients.119, 201 Whether or not this conclusion translates to pediatric patients

remains to be seen. TXA administration has been investigated in pediatric trauma in a military setting in

a retrospective study of 766 patients. This retrospective study of pediatric patients admitted to a North

Atlantic Treaty Organization military hospital in Afghanistan showed a significant survival advantage

conveyed by the use of TXA. The authors noted that a total of 66 patients received TXA; however, all

32
had more severe injuries, hypotension, coagulopathy, and acidosis compared with the non-TXA patients.

TXA was found to be independently associated with reduced mortality (OR 0.27; 95% CI, 0.85 - 0.89,

p=0.03).202 While this data is promising it is based on the outcomes of only 66 patients and hardly

constitutes a definitive answer. A large, multicenter, placebo controlled trial should be undertaken.

Antifibrinolytic dosing in pediatric surgery

See Table 1.

Costs and cost relationships between EACA and TXA

TXA and EACA are both less expensive than aprotinin.25 Though EACA is less potent than TXA, its

substantially lower costs as compared to TXA still enables EACA to be the more economical agent on

balance.29, 32 Raghunathan et al29 estimated a 225-fold direct pharmacy cost differential at their

institution on a head-to-head comparison between EACA and TXA ($2.40 for EACA versus $540.00 for

TXA), if an average 80-kg patient were to undergo a high-risk five hour cardiac surgery. Indirect costs

and the various risks versus benefits of blood product transfusion was not included in this estimation.

Falana et al32 in 2014 showed that EACA may have better value over TXA for reducing cardiovascular

surgical bleeding, considering the substantial cost difference and comparable efficacy and safety. A

2016 study evaluating EACA versus TXA efficacy in reducing postoperative transfusion rates also

compared the cost per surgery between agents in patients undergoing TKA.42 Their estimated

medication acquisition cost for EACA averaged $2.23 per surgery compared with TXA at $39.58 per

surgery, concluding that EACA utilization for TKA is comparable to TXA in all studied aspects at a lower

cost. In a second similar study in THA procedures, EACA was again comparable to TXA for reducing

transfusion rates while at a lower cost per surgery.39 Nonetheless, TXA is a relatively inexpensive and

widely available medication. These factors made it feasible to include the drug on the list of the

essential medicines by the WHO.3 The cost of TXA in the United States is on the order of $100 per 2 g

of TXA while the British National Formulary listed the price as $2.85 per 1 g.203, 204 When considering the

33
effects of significant blood loss, including transfusion costs, increased length of stay, increased operating

room time, laboratory costs, and associated comorbidities - though more expensive than EACA - the cost

of TXA is obviated and is still comparatively minimal.204, 205 In a 2016 study of TXA use in 139 THA

patients, the authors estimated savings of $314/patient just based on the decreased need for

transfusion and this figure did not account for savings due to reduced hospital stay.132 Another cost

analysis estimates that there is a total cost increase of 2 - 17 times when TXA is not used orthopedic

surgery.203

Future directions

Although TXA, aprotinin, and EACA have been widely used in a variety of surgical procedures

with significant beneficial effects observed on reducing perioperative blood loss and RBC transfusion

requirements, there are still many issues that need to be addressed by future investigations. As this

review elucidates, currently available antifibrinolytics need large comparative trials to address safety,

efficacy, and cost effectiveness, with a focus on non-cardiac surgeries. There are two ongoing large TXA

trials; one examining TXAs use in acute gastrointestinal bleeding (HALT-IT)206 and the other, its use in

traumatic brain injury (CRASH-3).207 Moreover, aprotinins safety needs to and will be monitored closely

with its reintroduction in Europe and Canada. Recent failures with ecallantide, a novel recombinant

peptide that inhibits plasma kallikrein, serve as a reminder that a drug that initially appears safe (when

first trialed in low bleeding risk patients) can ultimately be dangerous and contribute to higher mortality

especially when used in high risk patients.208 In addition to standard safety data monitoring, future

investigations of antifibrinolytics should focus on dosing issues such as timing (with incision or post-

anticoagulation in cardiac cases66), individualized dosing regimens based on interstitial plasmin activity

levels,209 optimal TXA dosing to reduce risk of seizures,148 renal effects of EACA, and population

pharmacokinetics.210

34
 Newer agents that are currently under investigation include the synthetic serine protease

inhibitor MDCO-2010. This drug is similar to aprotinin in that it broadly inhibits all serine proteases and

actively inhibits plasmin, plasma kallikrein, coagulation factors Xa and XIa, and activated protein C.

These properties make it a promising antifibrinolytic and its synthetic origin could potentially reduce

allergic reactions. In the lab MDCO-2010 was shown to be as potent as aprotinin in terms of inhibiting

fibrinolysis and was approved for use in a small phase II trial that studied patients undergoing CABG with

CPB.211, 212 Pharmacokinetics, coagulation effects, chest tube drainage, and transfusion requirements

were monitored and there was a significant reduction in transfusion requirements in the 24 treated

patients compared to the eight patients receiving placebo. Initial safety results were promising, but a

subsequent multicenter trial was terminated early due to an increased number of serious adverse

events noted in the treated patients. Final safety analyses from that multicenter trial are still pending

and will shed light on any adverse events directly linked to the drug.

A novel approach to the delivery of hemostatic agents is being studied using self-propelled

particles that can carry an agent to the damaged vasculature. Baylis et al213 developed a gas-generating

microparticle consisting of carbonate and TXA that was able to travel up to 1.5 cm/s and deliver the

therapeutic agent millimeters into the vasculature of wounds. When loaded with active thrombin, these

particles were shown to halt severe hemorrhage in multiple animal models of intraoperative and

traumatic bleeding.213 This research introduces intriguing areas for future investigation of enhanced

multimodal delivery of antifibrinolytics. Another potential contribution to this multimodal approach to

reducing perioperative bleeding loss is the development of biomaterials that have local hemostatic

activity, as seen in the work done by Sarda et al.214 They have shown promising results with their

investigation into the feasibility of combining TXA with hydroxyapatite (used in bone replacement) to

create a biomaterial that reduces bleeding locally, adding another feather to the quiver of hemostatic

agents.214

35
Summary

Antifibrinolytic agents have been part of the perioperative pharmaceutical armamentarium for

nearly thirty years while their use in the outpatient setting predates this by decades. In cardiac surgery,

well known for high requirements of allogeneic blood product transfusion, all three agents have proven

efficacy in reducing intraoperative and postoperative blood loss along with reducing the total amount of

transfusions. Aprotinins limited return to the cardiac operating rooms of Canada and parts of the

European Union will enable clinicians to continue to scrutinize its efficacy and potential adverse effects.

As a drug with efficacy that likely surpasses that of the lysine analogues, aprotinin use may continue to

expand in its indications as well as to various non-Canadian and non-European countries; currently in

the US it is only available for research purposes.215 In non-cardiac surgery, the use of TXA and EACA has

expanded greatly in the past decade; both of these agents are now being used routinely in a wide

spectrum of cases to attenuate blood loss. Both TXA and EACA are compelling from a cost perspective

due to their efficacy in reducing blood product usage. EACA is an inexpensive medication with a low risk

profile, making it an attractive alternative to TXA. For regions without access to TXA, EACA appears to

be an acceptable and more affordable alternative for many surgical arenas though TXA has greater

proven efficacy in trauma. Publication of various large trauma trials (CRASH-2119, MATTERs120, MATTERs-

II121) has led to the establishment of TXAs role in trauma surgery. See Table 3 for comparisons between

TXA, EACA, and aprotinin.

Antifibrinolytics have an overall excellent safety profile but, as with any drug, thoughtfulness

must always be applied prior to administration. There is a theoretical risk of severe life-threatening

thrombosis in patients with a known hypercoagulable disorder or those with a clinical condition

predisposing them to a hypercoagulable state. From the perspective of clinicians managing

perioperative bleeding, the goal should be to have the patient remain in hematologic homeostasis.

Administering an antifibrinolytic in the face of chronic and possibly necessary fibrinolysis can upset this

36
delicate balance and generate potentially catastrophic thrombosis. Aside from the unique concerns

involving aprotinin, the safety of antifibrinolytics is primarily derived as a secondary outcome or by

adverse event monitoring in studies that are not powered or designed to detect these issues. The

majority of thrombotic complications related to antifibrinolytics have been published as case reports. In

the many decades of their use, it was not until 2016 that a trial specifically designed to assess the

thrombotic complications of one of the antifibrinolytics was published. Though the findings of Myles et

al108 regarding TXA are reassuring, this trial was only conducted in cardiac surgery patients; there are a

myriad other surgical venues where patients are receiving antifibrinolytics where the safety of these

agents has not been fully investigated. As the use of antifibrinolytics becomes increasingly common,

perioperative physicians should maintain a high level vigilance regarding their potential overuse or for

the development of a cavalier attitude regarding these drugs apparent safety. The vast majority of

patients do not have any complications related to their use, but the potential complications when

misused or overdosed can be serious.

37
Figure legends

Figure 1: Lysine, epsilon aminocaproic acid, and tranexamic acid molecular structures. Note the

structural similarity to the amino acid lysine from which they are derived.

Figure 2: Schematic diagram of mechanism of action of antifibrinolytic agents on fibrinolysis in

the intravascular space. Normal fibrinolysis (A, top of inset): plasminogen is converted to plasmin by

tissue plasminogen activator (TPA) along with the binding of lysine which allows this ternary complex to

attach to polymerized fibrin which also then activates plasminogen and releases plasmin. Plasmin is

easily released from its fibrin-binding site and the naturally occurring inhibitor (2-antiplasmin)

neutralizes plasmin. However, if plasmin is created in its normal position associated with fibrin, then 2-

antiplasmin is able to only minimally inhibit this process. Fibrin catalyzes the activation of plasminogen

by TPA and since it binds both TPA and plasminogen on its surface, fibrin not only enhances the

generation of plasmin but also localizes it to the area of the thrombus. Inhibited fibrinolysis (B, bottom

of inset): EACA and TXA modulate the fibrinolytic pathway in the intravascular space by binding to the

lysine-binding site of plasminogen associated with the TPA / plasminogen / plasmin complex. EACA and

TXA, by binding competitively to this complex, inhibit the binding of this complex molecule onto fibrin.

This binding inhibition prevents plasmin release, allowing for the stability of fibrin clots.

Figure 3:
#
Category A1-B evidence, ^Category A3-B evidence recommendations from American Society of

Anesthesiologists Task Force on Perioperative Blood Management.33

*Based on recommendations from the Neurocritical Care Society's Multidisciplinary Consensus

Conference and 2012 American Stroke Association guidelines statement (for patients with an

unavoidable delay in obliteration of aneurysm, a significant risk of rebleeding, and no compelling

medical contraindications); Low quality evidence / weak recommendation.55

38
 Abbreviations: CPB, cardiopulmonary bypass; DHCA, deep hypothermic circulatory arrest; EACA, epsilon

aminocaproic acid; TXA, tranexamic acid; TKA, total knee arthroplasty; THA, total hip arthroplasty; aSAH,

aneurysmal subarachnoid hemorrhage.

Table 1 - Adult and Pediatric EACA and TXA Dosing Strategies

EACA TXA
65, 216
Cardiac surgery - 1) Butterworth et al protocol High-bleeding potential High-dose regimen
28 217 100
Adult Loading dose - at induction BART Study protocol ; Hodgon et al ; Sharma et al
a) 80 mg/kg over 20 min, or Loading dose at induction
b) 60 mg/kg over 20 min + 10 mg/kg in CPB prime 5 ml test dose from total dose of 30 mg/kg (mixed in 250 ml NS) over 10 min - followed
Loading dose - after heparin administration by balance of total
70 mg/kg over 20 min + 2 mg/kg in CPB prime
Maintenance Maintenance
30 mg/kg/h (x 4h total) 16 mg/kg/h, until sternotomy closure
28 217
2) BART Study protocol Low-bleeding potential Low-dose regimen
Loading dose at induction Loading dose at induction
200 mg test dose over 10 min followed by 9800 mg 10 mg/kg + 1 mg/kg in CPB prime
Maintenance Maintenance
2 g/h until sternotomy closure 1 mg/kg/h

3) Greilich et al protocol67 Renal dosing adjustment to achieve plasma concentration of 100mg/L 133
Loading dose at induction % of nl GFR 100% 75% 50% 25% 10% 5% 1%
100 mg/kg + 5 g in CPB prim Maintenance 16 12 6 5 1.6 0.8 0.16
Maintenance Infusion rate
30 mg/kg/h (mg/kg/hr)

Cardiac surgery - Older pediatric Neonates24 Weight adjusted schema220

Pediatric patients Loading dose Loading dose: 5-40kg: 6.4 mg/kg
Loading dose 40 mg/kg Maintenance (mg/h)
75 mg/kg over 10 Maintenance 5kg: 15.5 25kg: 55.2
minutes, 30 mg/kg/hour + pump prime 10kg: 26.8 30kg: 63.9
repeated on concentration of 100 mg/L 15kg: 36.9 35kg: 72.2
initiation of CPB218, 20kg: 46.3 40kg: 80.4
219

Maintenance
75 mg/kg/h218, 219
Spine surgery - Bolus Bolus
Adult 100 mg/kg over 15 minutes prior to incision45, 47, 50 10 - 20 mg/kg
Maintenance Maintenance
10 mg/kg/h for duration of surgery45, 47, 50 10 - 100 mg/h

Spine surgery - <25 kg: 100 mg/kg loading dose and 40 mg/kg/h infusion210
Pediatric 25-50 kg: 100 mg/kg loading dose and 35 mg/kg/h infusion210
50 kg: 100 mg/kg loading dose and 30 mg/kg/h infusion210

THA Bolus
10 - 20 mg/kg (maximum 1 g) - preincision122
Maintenance
10 20 mg/kg for 3 - 12 h122
TKA 10 g dose over 10 min at start of implant cementation42 Bolus
10 - 20 mg/kg (maximum 1 g), ideally given 5 20 min prior to tourniquet deflation122
Maintenance
10 20 mg/kg for 3 - 12 h122
aSAH Bolus
5 - 10 g either in the ED or during transportation221
Maintenance
2 g/h until time of endovascular procedure (for < 72 h max) 221
OLT 16 mg/kg/h from induction until reperfusion8

Trauma Bolus
1 g over 10 min119-121, 202
Maintenance
1 g over 8 h119-121, 202

PPH in C/S 0.5 - 1 g, 30 min preincision127

Craniosynostosis 50 mg/kg initial dose, followed by 5 mg/kg/h infusion194

39
Abbreviations: EACA, epsilon aminocaproic acid; TXA, tranexamic acid; CPB, cardiopulmonary bypass; BART, Blood Conservation Using Antifibrinolytics in a
Randomized Trial; NS, normal saline; THA, total hip arthroplasty; TKA, total knee arthroplasty; aSAH, aneurysmal subarachnoid hemorrhage; OLT, orthotopic liver
transplantation; C/S, cesarean section; CrCl, creatinine clearance; GFR, glomerular filtration rate; ED, emergency department; PPH, post-partum hemorrhage; nl,
normal.

40
Table 2 Precautions / contraindications to perioperative antifibrinolytic use
Clinical scenario /
patient condition
Allergy or hypersensitivity
History of signicant venous
or arterial thrombosis or
thromboembolic event
Inherited hypercoagulable
states
Acquired and non-primary
hypercoagulable states
(including risk factors for)
Renal insufciency / AKI
Electrolyte disturbance
Concurrent subarachnoid
hemorrhage or traumatic
brain injury
History of seizure disorder or
poorly controlled seizure
disorder
Concomitant treatment with
other procoagulants
Disseminated intravascular
coagulation
Pregnancy
Miscellaneous
Abbreviations: KIU, kallikrein inhibitor units; TXA, tranexamic acid; EACA, epsilon aminocaproic acid; HIV, human immunodeficiency virus; HAART, highly
active antiretroviral therapy; CV, cardiovascular; AKI, acute kidney injury; N/R, not reported.
a
Category B = No risks have been found in humans. bCategory C = Not enough research has been done to determine if these drugs are safe.
TXA EACA Aprotinin
Possible anaphylaxis with use90 Possible anaphylaxis with use Possible anaphylaxis, especially with re-
Hypersensitivity to active compound Hypersensitivity to active compound exposure <12 months of use173
Benzyl alcohol hypersensitivity (used in Hypersensitivity to active compound
IV formulation) Absolute contraindication with known
Paraben hypersensitivity (used in oral +IgG antibody versus aprotinin155
preparation) Contraindicated if exposure or fibrin
sealant product exposure within prior 12
months155, 173
1 ml (10,000 KIU) test dose
recommended155
Deep vein thrombosis106, 137, 222 Use similar precautions / similar Use similar precautions / similar
Pulmonary embolism98, 137, 139, 222 concerns associated with TXA concerns associated with TXA
Coronary thrombosis222significant
consideration should be taken with
coronary stenting
Cerebral thrombosis136, 222
Acute renal cortical necrosis141
Central retinal vein or artery
obstruction223
Antithrombin deciency222 Use similar precautions / similar Use similar precautions / similar
Factor V Leiden mutation222 concerns associated with TXA concerns associated with TXA
Prothrombin gene mutation222
Protein C or S deciencies222
Dysbrinogenemias222
Factor XII deciency222
Prior thrombosis/thromboembolism90 Use similar precautions / similar Use similar precautions / similar
Malignancyespecially advanced concerns associated with TXA concerns associated with TXA
disease222
Antiphospholipid syndrome
Recent major operative procedure222
Prolonged immobilization
Prior heparin use (heparin-induced
thrombocytopenia with thrombosis)
Hormone replacement therapy / oral -
contraceptive use
Nephrotic syndrome222
Polycythemia vera; thrombocythemia
HIV infection/HAART therapy134
Congestive heart failure
Central venous catheters/hardware
Pregnancy
Bevacizumab, tamoxifen, or testosterone
therapy
Primarily renal excretion and toxicity Hyperkalemia risk with infusion Association with postoperative renal
potential increased with renal especially if concomitant renal dysfunction155
insufciency141 insufficiency73, 83, 84 Concurrent aminoglycoside use
Reports of rhabdomyolysis induced
AKI79
Traumatic brain injury is independently Traumatic brain injury is independently N/R
associated with hypercoagulable state; associated with hypercoagulable state;
only short (<72 hours) course only short (<72 hours) course
recommended26, 30, 224 recommended54, 225
TXA has epileptogenic potential; seizure N/R N/R
activity has been reported in use in
cardiac surgery108, 145
Thrombosis risk increased with use of Use similar precautions / similar Use similar precautions / similar
Factor IX Complex and anti-inhibitor concerns associated with TXA concerns associated with TXA
coagulant concentrates
Risk of thrombosis; may require Use similar precautions / similar Use similar precautions / similar
concomitant heparin use71 concerns associated with TXA concerns associated with TXA
aCategory B agent but no well-controlled bCategory C; no animal studies; no Category B - no evidence of risk in
studies of use during pregnancy; use in controlled data in human pregnancy89 humans
pregnancy should be limited90, 98 Only recommended when benefit>risk89
Chromatopsia and visual impairment has Multiple health regulatory agencies
been reported in use in hemophiliacs226 warn against use when coronary artery
surgery is combined with other CV
procedures155
41
 Table 3 - Advantages and disadvantages of EACA, TXA, and aprotinin
EACA
Advantages
Lowest cost of all three agents39, 42
Positive recommendation for short
term use in aneurysmal SAH54, 55
Worldwide availability
Possibly more efficacious for
complex orthopedic procedures227
Topical availability62, 63
Disadvantages
Conflicting data on benefit in
orthopedic procedures30, 230, 231
7-10x less potent than TXA228
Paucity of literature regarding use in
obstetrics
Category C in pregnancy89
Associated with fatal gasping
syndrome in neonates and low-
birth weight infants89
EACA versus TXA in Cardiac- and Non-cardiac surgery context27, 30
Non-cardiac surgery
No overall difference in transfusion rate
No overall difference in volume of blood
transfused
No overall difference in reoperation rates for
bleeding
No mortality, MI, stroke differences
Greater volume of positive literature for TXA in
trauma as compared to EACA4, 119-121
Greater volume of positive literature for TXA
use in orthopedic surgery125, 126, 229
Topical TXA possibly equally efficacious to IV
TXA in orthopedics130, 131
Topical TXA or EACA may mitigate against
VTE62, 63, 140
Abbreviations: EACA, epsilon aminocaproic acid; TXA, tranexamic acid; UK, United Kingdom; MI, myocardial infarction; SAH, subarachnoid
hemorrhage; OTL, orthotopic liver transplantation; IV, intravenous; DHCA, deep hypothermic circulatory arrest; PE, pulmonary embolism; DVT,
deep vein thrombosis; CABG, coronary artery bypass grafting; POCD, postoperative cognitive dysfunction; CKD, chronic kidney disease; AKI,
acute kidney injury.
TXA Aprotinin
Advantages Advantages
Ample literature on efficacy in Greater efficacy in cardiac surgery as
trauma compared to EACA/TXA27, 30
High-quality evidence of low
thromboembolic risk in CABG
surgery108
Positive recommendation for
short term use in aneurysmal
SAH54
More potent than EACA228
Reduced transfusion rates in OTL8
Worldwide availability
Minimal protein binding90
No significant metabolites229
Topical availability
Category B in pregnancy
Disadvantages Disadvantages
More expensive than EACA18, 39, 203 Limited availability to UK, Sweden,
Epileptogenic potential108, 217 Netherlands, Canada6
Higher rate of seizures when used Possible greater risk for
with DHCA232 postoperative renal dysfunction27
Needs dose reduction in renal
insufciency141
Can cause false-negative D-dimer
in context of true PE / DVT139, 233
Cardiac surgery
No difference in transfusion rates32, 41, 230
No difference in blood volume lost during
postoperative period27, 55
TXA only agent examined prospectively
for thromboembolic complications108
Possible less POCD with TXA compared to
EACA72
Seizure risk with TXA
TXA needs dose adjustment in CKD
EACA possibly associated with
hyperkalemia and/or AKI in susceptible
patient
42
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65
 Lysine

H2N

OH
NH2

EACA

H2N

OH

TXA

H2N CH2 COOH

66
 Fibrin
Stable fibrin clot =
hemostasis

Aprotonin

Plasminogen Plasmin

EACA / TXA competitively inhibit activation

of plasminogen to plasmin; see inset below
Fibrin degradation
products
Tissue plasminogen activator (TPA)
Fibrinolysis = bleeding

TPA Plasminogen
A: Normal fibrinolysis
TXA / EACA binding site
(lysine site)

Polymerized
fibrin

Plasmin
Fibrin
degradation
products (FDP)

Fibrin

Plasminogen

TPA B: Inhibited fibrinolysis

EACA or TXA

Fibrin

Fibrinolysis is inhibited: EACA or TXA binds to

fibrin-binding site on plasminogen. This binding
Fibrin
prevents67activation to plasmin.
68