Intravenous Tranexamic Acid Versus Topical Aminocaproic Acid: Which Method Has the Least Blood Loss and Transfusion Rates?

Abstract

Introduction
Since the advent of antifibrinolytics, blood transfusions and their associated complications in total joint arthroplasty have decreased. Few studies have compared different antifibrinolytic types with respect to blood loss and transfusion rates. We sought to compare the blood loss and transfusion rates between epsilon-aminocaproic acid (EACA), tranexamic acid (TXA), and control.

Methods
A total of 564 patients underwent primary total hip or total knee arthroplasty at our institution. Patients were divided into 3 groups: 183 EACA, 204 TXA, and 177 control. Patient demographics, hemoglobin, transfusion rates, and blood loss were collected.

Results
Patient preoperative variables were similar. The control group had a mean estimated blood loss (EBL) of 1.48 L, with 51 units of packed red blood cells (pRBCs) given and 14.7% of patients receiving a blood transfusion. The EACA group had an EBL of 1.33 L, with 20 pRBCs given and 10.9% of patients receiving a transfusion. The TXA group had an EBL of 1.05 L, with 3 pRBCs transfused in 0.98% of patients. Compared with the control group, blood loss (P = 0.0014; P < 0.0001), number of pRBCs given (P = 0.007; P < 0.0001), and number of patients transfused (P = 0.012; P < 0.0001) were significantly lower in the EACA and TXA groups, respectively. TXA had significantly lower blood loss (P < 0.0001), lower number of tranfusions (P = 0.005), and less patients transfused (P = 0.003) compared with EACA.

Conclusion
Our study reports lower blood loss, transfusion rates, and number of patients needing transfusion with both EACA and TXA in the setting of total joint arthroplasty. When comparing between EACA and TXA, TXA had lower blood loss, transfusion rates, and number of patients requiring transfusion.

Full text

Research Article
Intravenous Tranexamic Acid
Versus Topical Aminocaproic Acid:
Which Method Has the Least Blood
Loss and Transfusion Rates?
Abstract
Introduction: Since the advent of antifibrinolytics, blood
transfusions and their associated complications in total joint
arthroplasty have decreased. Few studies have compared
different antifibrinolytic types with respect to blood loss and
transfusion rates. We sought to compare the blood loss and
transfusion rates between epsilon-aminocaproic acid (EACA),
tranexamic acid (TXA), and control.
Methods: A total of 564 patients underwent primary total hip or
total knee arthroplasty at our institution. Patients were divided
into 3 groups: 183 EACA, 204 TXA, and 177 control. Patient
demographics, hemoglobin, transfusion rates, and blood loss
were collected.
Results: Patient preoperative variables were similar. The control
group had a mean estimated blood loss (EBL) of 1.48 L, with 51
units of packed red blood cells (pRBCs) given and 14.7% of
patients receiving a blood transfusion. The EACA group had an
EBLof1.33L,with20pRBCsgivenand10.9%ofpatients
receiving a transfusion. The TXA group had an EBL of 1.05 L,
with3pRBCstransfusedin0.98%ofpatients.Comparedwith
the control group, blood loss (P= 0.0014; P,0.0001), number
of pRBCs given (P= 0.007; P,0.0001), and number of
patients transfused (P= 0.012; P,0.0001) were significantly
lower in the EACA and TXA groups, respectively. TXA had
significantly lower blood loss (P,0.0001), lower number of
tranfusions (P= 0.005), and less patients transfused (P=0.003)
compared with EACA.
Conclusion: Our study reports lower blood loss, transfusion
rates, and number of patients needing transfusion with both
EACA and TXA in the setting of total joint arthroplasty. When
comparing between EACA and TXA, TXA had lower blood loss,
transfusion rates, and number of patients requiring transfusion.
Zachary C. Lum, DO
Martin A. C. Manoukian, BS
Christopher S. Pacheco, BA
Alexander J. Nedopil, MD
Mauro Giordani, MD
John P. Meehan, MD
From the Department of
Orthopaedics, Adult Reconstruction
Section, University of California:
Davis Medical Center, Sacramento,
CA.
Correspondence to Dr. Lum:
zacharylum@gmail.com
JAAOS Glob Res Rev 2018;2:e072
DOI: 10.5435/
JAAOSGlobal-D-18-00072
Copyright © 2018 The Authors.
Published by Wolters Kluwer Health,
Inc. on behalf of the American
Academy of Orthopaedic Surgeons.
This is an open access article
distributed under the Creative
Commons Attribution License 4.0
(CCBY), which permits unrestricted
use, distribution, and reproduction in
any medium, provided the original
work is properly cited.

Blood loss and transfusions in
total joint arthroplasty have been
revolutionized by the arrival of anti-
fibrinolytics. Before their use, studies
had routinely reported transfusion
rates of 10% to 24%, with direct and
indirect costs up to $1,200.
1-5
With
addition of these medications, topi-
cal or intravenous, current transfu-
sion rates have decreased and can
range from 1% to 10%.
1-5
Tranexamic acid (TXA) and
epsilon-aminocaproic acid (EACA)
belong to the lysine analog class of
antifibrinolytic agents. They have
similar mechanisms of action, with
TXA demonstrating a 6- to 10-fold
increased affinity in binding plas-
minogen compared with EACA.
6,7
Because of its high affinity, TXA has
mostly replaced EACA as the pre-
dominant lysine analog used for
major orthopaedic procedures.
Few studies have compared differ-
ent antifibrinolytic types with respect
to blood loss and transfusion rates.
We sought to compare whether
EACA or TXA had the least amount
of blood loss and transfusion rates
with a control group for comparison.
We hypothesized that although there
may be a difference in blood loss,
there would be no difference with
regard to transfusion rates or units of
blood given.
Methods
From January 2008 to June 2016, a
retrospective chart review of 564
patients who underwent primary
total hip (THA) or total knee ar-
throplasty (TKA) was performed by 2
surgeons at our institution. Patients
were sequentially selected via the
CPT code for primary THA (ie,
27130) or primary TKA (ie, 27447).
For our control cohort, patients were
selected from an older cohort before
hospital approval of antifibrinolytic
administration. Patients were ex-
cluded for preoperative anemia, for
revision surgery, osteoarthritis from a
secondary disease (eg, inflammatory,
posttraumatic), previous surgery to
the surgical side, active infection,
or history of bleeding or clotting
disorders.
Patients were divided into 3 groups.
The EACA group received 5 g/100 mL
of saline mixture applied topically.
This mixture was applied before
tourniquet release and left in the
wound for at least 1 minute. The TXA
group received 1 g/10 mL IV or 3
g/100 mL topically. Patients received
primarily IV TXA, unless the patient
had atrial fibrillation, cardiac stents,
previous history of venous thrombo-
embolic (VTE) disease, or stroke. Ten
patients received topical TXA.
Perioperative management was the
same for the EACA and TXA groups.
For these 2 cohorts, VTE prophylaxis
postoperatively included aspirin 325
mg daily or warfarin with goal INR 1.5
to 2.0. Patients primarily received
aspirin unless they have significant VTE
risk factors such as previous recent VTE
within 6 months or pulmonary embo-
lism with decompensation. The control
group received surgery earlier in the
date range and was administered
enoxaparin or warfarin with the same
INR goals. This was before our anti-
coagulation committee’s approval of
aspirin as a form of VTE prophylaxis.
The medial parapatellar approach
was used for all TKAs, and the
posterolateral approach was used for
all THAs. One surgeon performed the
gap balancing technique for TKAs
and used primarily EACA for hemo-
stasis; the other surgeon performed
measured resection and used pri-
marily TXA. Both surgeons are fel-
lowship trained in adult reconstruction
at the same fellowship.
Patient demographics, including age,
sex, weight, height, and body mass
index (BMI), were collected. Preoper-
ative hemoglobin and subsequent
postoperative hemoglobins were ob-
tained until discharge. Transfusions
rates and blood loss were calculated
using the Gross equation (estimated
blood loss [EBL] = estimated blood
volume [EBV] ·[Hct
0
2Hct
f
]/Hct
AV
).
Statistical Analysis
Patients receiving no antifibrinolytic
drug were considered the control
group for analysis, whereas the pa-
tients receiving an antifibrinolytic
were categorized in the TXA or
EACA group. Continuous variables
were described using mean values and
SDs and compared using the Student
t-test. Categoric variables were shown
as frequency and percentages and
were compared using the chi-square
test. Preoperative analysis for age,
female sex, preoperative hemoglobin,
and BMI was performed. Postopera-
tive hemoglobins were trended and
EBV was predicted using sex and
height, and entered into the EBL
equation using the Gross calcula-
tion for blood loss (EBL = EBV ·
[Hb
0
2Hb
f
]/Hb
AV
).
Results
A total of 564 patients underwent
THA or TKA, with 177 patients
receiving no antifibrinolytic, 183 in
the EACA cohort, and 204 in the
TXA cohort. Patient preoperative
variables were similar (Table 1). The
Dr. Meehan or an immediate family member is a member of a speakers’bureau or has made paid presentations on behalf of DePuy and A
Johnson & Johnson Company; serves as a paid consultant to OrthAlign; and has received research or institutional support from DePuy and
A Johnson & Johnson Company. None of the following authors or any immediate family member has received anything of value from or has
stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Lum,
Manoukian, Pacheco, Dr. Nedopil, and Dr. Giordani.
Tranexamic Acid Versus Aminocaproic Acid
2Journal of the American Academy of Orthopaedic Surgeons

average age of the control group was
61.9 years (21 to 90 years), EACA
group was 62.7 years (25 to 88
years), and the TXA group was 65
years (24 to 85 years). No difference
was found between the control and
EACA groups (P= 0.4625); however,
the TXA group was significantly older
than both the EACA and control
groups (P=0.02;P= 0.0026).
The percentage of female in the
control, EACA, and TXA groups
were 60.3%, 62.7%, and 51.7%,
respectively, and demonstrated no
difference between the control and
EACA groups (P= 0.2694), control
and TXA groups (P= 0.0899), and
EACA and TXA groups (P= 0.5694).
BMI in the control, EACA, and TXA
cohorts were 30.2 kg/m
2
(18.4 to
49.3 kg/m
2
), 30.2 kg/m
2
(17.4
to 45.6 kg/m
2
), and 30.0 kg/m
2
(18.2to45.6kg/m
2
), respectively, and
demonstrated no difference between
the control and EACA groups (P=
0.9619), control and TXA groups (P=
0.7137), and EACA and TXA groups
(P= 0.5694). Preoperative hemo-
globin in the control group measured
13.6 g/dL (11.3 to 19.1), EACA
group 13.8 g/dL (11.1 to 18.5), and
TXA group 13.8 g/dL (11.1 to 17.0).
No difference was found between the
control and EACA groups (P=
0.1225), control and TXA groups
(P= 0.0526), and EACA and TXA
groups (P= 0.7227).
The control group had an EBL of
1,480 mL, with 51 units of packed red
blood cells (pRBCs) given and 14.7% of
patients receiving a blood transfusion
(Table 2). The EACA group had an
EBL of 1,330 mL with 20 pRBCs given
and 10.9% of patients receiving a
transfusion. The TXA group had an
estimated 1,050 mL blood loss, with 3
units of pRBCs transfused in 0.98% of
patients. Compared with the control
group, blood loss (P= 0.0014; P,
0.0001), number of pRBCs given (P=
0.007; P,0.0001), and number of
patients transfused (P= 0.012; P,
0.0001) were significantly lower in the
EACA and TXA groups, respectively.
Thus, both antifibrinolytics resulted in
lower blood loss and transfusion rates.
When comparing the EACA versus
TXA groups, the TXA group had sig-
nificantly less blood loss (1,330 mL ver-
sus 1,050 mL; P,0.0001), lower
number of tranfusions (10.9% versus
1.47%; P= 0.005), and less patients
transfused (6.56% versus 0.98%; P=
0.003) compared with the EACA group.
Discussion
Antifibrinolytics have significantly
lowered the transfusion rates and
associated transfusion-related com-
plications in total joint arthroplasty.
Table 1
Preoperative Values of Control, Aminocaproic Acid, and Tranexamic Acid
Category Control PValue EACA PValue TXA
No. patients 177 —183 —204
Age 61.9 (21-90) 0.4625 62.7 (25-88) 0.02 65 (24-85)
Sex 60.3% female 0.2694 54.6% female 0.5694 51.7% female
BMI (kg/m
2
) 30.2 (18.4-49.3) 0.9619 30.2 (17.4-45.6) 0.661 30.0 (18.2-45.6)
No. THA 76 (42.9%) —77 (42.1%) —105 (51.5%)
Preoperative Hgb (g/dL) 13.6 (11.3-19.1) 0.1225 13.8 (11.1-18.5) 0.7227 13.8 (11.1-17.0)
BMI = body mass index, EACA = epsilon-aminocaproic acid, THA = total hip arthroplasty
Table 2
Results of Control, Aminocaproic Acid, and Tranexamic Acid
Category Control PValue EACA PValue TXA
No. patients 177 —183 —204
Preoperative Hgb (g/dL) 13.6 (11.3-19.1) 0.1225 13.8 (11.1-18.5) 0.7227 13.8 (11.1-17.0)
Hgb POD1 10.5 (5.7-15.6) —11.1 (6.6-16.6) —11.3 (7.9-15.4)
Hgb POD2 9.85 (6.7-14.9) —10.3 (7.3-14.9) —11.0 (7.5-14.7)
Blood loss (L) 1.48 (0.20-3.40) 0.00135 1.33 (0.44-3.03) ,0.0001 1.05 (0.31-2.90)
Units given 51 (28.8%) 0.00701 20 (10.9%) 0.00471 3 (1.47%)
Patients transfused 26 (14.7%) 0.01201 12 (6.56%) 0.00341 2 (0.98%)
EACA = epsilon-aminocaproic acid, POD = postoperative day
Zachary C. Lum, DO, et al
November 2018, Vol 2, No 11

Many studies have reported lower
transfusion rates with intravenous or
topical TXA compared with pla-
cebo.
1-4,6-8
In addition, studies in-
volving EACA have also reported
lower transfusion rates in TJA.
1-4,8
Our results agree that both anti-
fibrinolytics EACA and TXA signif-
icantly decrease transfusion rates
compared with placebo control (P=
0.012; P,0.0001), respectively.
Our cohort of 564 patients divided
into 3 groups of 184 EACA, 204
TXA, and 177 control reported less
blood loss and blood transfusions in
the antifibrinolytics versus control. In
addition, we were surprised to have
found a significantly lower blood loss
and transfusion rate in favor of TXA
versus EACA.
Few studies directly compare blood
loss and transfusion rates between
EACA and TXA. Churchill et al
3
retrospectively compared transfu-
sion rates between EACA, TXA,
and a control group in 2,922 TKAs.
They reported that significantly
fewer patients received blood trans-
fusion in the EACA and TXA groups
(2.8%, P,0.0001; 3.2%, P,
0.0001) compared with the control
group (10.8%). On their compari-
son, they did not report any differ-
ence in transfusion rates between the
two antifibrinolytics (P= 0.822).
Their group also retrospectively in-
vestigated transfusion rates between
the 2 antifibrinolytics and a control
in 1,799 THAs.
2
They also found
significantly lower transfusion rates
in the EACA group (6.8%; P,
0.0001) and TXA group (9.7%; P,
0.0001) compared with the control
group (24.7%), with no difference in
transfusion rates between the two
antifibrinolytics (P= 0.074). Although
our results confirmed that both anti-
fibrinolytics significantly lowered
transfusion rates, we reported a sig-
nificant difference in transfusion
rates between EACA and TXA. One
of the discrepancies noted was their
preoperative variables. In their TKA
cohort, the TXA cohort was signifi-
cantly older (65.8 versus 63.9; P=
0.001), had higher number co-
morbidities (P= 0.0096), and had
significantly lower preoperative hemo-
globin than EACA (P,0.0001), all
surrogates for increased blood loss and
transfusion rates. In their THA cohort,
the TXA cohort had significantly lower
preoperative hemoglobin than EACA
(P= 0.02), a risk factor for higher
transfusion rates and blood loss. These
confounding variables may skew the
results of their data in favor of EACA.
Although our number of comorbidities
was not recorded, our preoperative
hemoglobin and BMI were not differ-
ent. Our age groups favored against
TXA, with a higher age in TXA
compared with EACA and control (65
versus 62.7 and 61.9; P= 0.02).
There are 2 level 1 studies com-
paring EACA, TXA, and placebo in
TKA. Camarasa et al
8
randomized
128 patients undergoing primary
TKA to receive TXA, EACA, or
placebo. Powered only to detect all
antifibrinolytics combined versus
control, they reported significantly
lower transfusion rates and units
(7.5% versus 38.3%; P,0.001).
They had 35 patients who received
TXA and 32 patients who received
EACA. When comparing between
these 2 groups, 2.8% of TXA patients
received a transfusion compared with
12.5% of EACA. Although this dif-
ference seems large, this was not found
to be significant, possibly because of
the lack of power and sample size.
This scenario was mentioned in their
study. Compared with our data, the
overall percentages of transfused pa-
tients are similar in TXA (2.8% versus
0.98%) and EACA (12.5% versus
6.56%). Although their level 1 study
could not find a difference in trans-
fusion rates between TXA and EACA,
they were not powered to detect a
difference.
Boese et al
1
performed a recent level
1 randomized control trial compar-
ing EACA versus TXA in TKA in 194
patients. Although they reported that
both arms of their study had zero
transfusions, blood loss in the TXA
was significantly lower than EACA
at 144.2 mL (P= 0.031), although
this was deemed to be clinically not
significant. One important fact is that
their power analysis to detect differ-
ences was much lower than their
recruitment study size, which may
result in lower numbers reported.
The strengths of our study are our
relatively larger sample size at a single
tertiary level 1 center. Our surgeons
used the same approaches with simi-
lar perioperative protocols. We
found no difference in preoperative
variables. In addition, our average
hospital length of stay was longer
than all the other comparison studies,
which means we may have captured
more accurate data regarding true
blood loss.
Our study had several limitations.
Besides being a retrospective study
chart review, one surgeon used pri-
marily one antifibrinolytic, EACA,
which may place our results at risk of
bias. Although most perioperative
protocols were standardized, the an-
ticoagulation was not. Some patients
received aspirin; others received war-
farin, which can affect wound drain-
age and potentially perioperative
blood loss. This scenario was difficult
to control for, and all of the previ-
ously cited EACA versus TXA com-
parison studies did not account for
this variable as well. In addition, most
patients received intravenous TXA
compared with topical EACA.
Although other studies have demon-
strated no difference between topical
and intravenous antifibrinolytics, the
route of administration was not the
same in all cases. Last, we grouped
THA and TKA together because both
arthroplasty types can have differing
transfusion rates. Although our TXA
cohort had a higher percentage of
THAs, this would have strengthened
our study because THA has an in-
creased risk of transfusion (51.5%
Tranexamic Acid Versus Aminocaproic Acid
4Journal of the American Academy of Orthopaedic Surgeons

versus 42.1%). Last, we used 5 g of
EACA, whereas some studies used
100 mg/kg or 7 g; we used 1 g of TXA,
whereas some studies used 10 mg/kg or
2 doses, possibly resulting in under-
dosing. Interpretation of these results
may suggest that a higher EACA dos-
ing is necessary to get a similar clinical
benefit compared with TXA.
Conclusion
Antifibrinolytics in total joint ar-
throplasty have revolutionarily de-
creased blood loss, transfusion rates,
and their associated complications.
The decision to use one is obvious,
however which type is not clear. We
reported TXA to have less blood
loss, transfusion rates, and number
of transfusions given compared with
EACA. These data dispute other
studies that demonstrate no differ-
ence in blood loss between the two
medications. Additional studies
with higher sample sizes may be
required to discern whether a dif-
ference exists between the two
antifibrinolytics.
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MC, Truchan SL, Anderson MJ:
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Zachary C. Lum, DO, et al
November 2018, Vol 2, No 11