Original Article

Local administration of tranexamic acidin off-pump coronary artery bypass

Asian Cardiovascular & Thoracic Annals
20(6) 658–662
ß The Author(s) 2012
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DOI: 10.1177/0218492312441472
aan.sagepub.com

Masakazu Aoki, Yasuhide Okawa, Yoshihiro Goto, Shinji Ogawa
and Hiroshi Baba

Abstract
Purpose: We administered tranexamic acid locally to patients undergoing off-pump coronary artery bypass, to investigate the hemostatic effects and safety.
Patients and methods: The subjects were 100 consecutive patients who underwent off-pump coronary artery bypass
between July 2009 and January 2011. We assigned 50 patients in the early phase, in which tranexamic acid was not
employed, to group N, and 50 in the late phase, in which tranexamic acid was employed, to group T. In group T, 10 mL ofa solution containing 1 g of tranexamic acid in was sprayed into the pericardial cavity and mediastinum before thesternum was closed. We compared the volume of postoperative blood loss, blood transfusion volume, and complications
between the 2 groups.
Results: The volume of blood loss in 24 h after intensive care unit admission was 492 mL in group N and 303 mL ingroup T (p < 0.0001); the decrease in blood loss in the group receiving tranexamic acid was approximately 40%. There
was no significant difference in the blood transfusion volumes. There were no side effects of tranexamic acid.
Conclusion: In patients undergoing off-pump coronary artery bypass, local administration of tranexamic acid may
decrease the volume of postoperative blood loss. The local administration method is simple, inexpensive, and safe.

Keywords
Antifibrinolytic agents, blood loss, surgical, blood transfusion, coronary artery bypass, off-pump, tranexamic acid

Introduction

Patients and methods

Postoperative hemorrhage related to open heart
surgery increases the rates of complications and mortality, representing a serious issue.1 Systemic administration of antiﬁbrinolytic agents has been commonly
employed in the ﬁeld of cardiac surgery, and manystudies have reported their hemostatic eﬀects.2
However, many cases of serious complications related
to systemic administration have been reported. The
BART trial in 2008 showed that aprotinin administration increased the mortality rate. Subsequently, thesale of this agent was discontinued.3 On the other
hand, previous studies have reported the local administration of antiﬁbrinolytic agents.4.5 This therapy has
been highlighted since the BART trial, due to its low
incidence of side eﬀects.6,7 In this study, we locallyadministered an antiﬁbrinolytic agent, tranexamic
acid, to patients undergoing oﬀ-pump coronary
artery bypass (OPCAB) to investigate its hemostaticeﬀects and safety.

The study enrolled 100 consecutive patients who underwent OPCAB between July 2009 and January 2011. We
assigned 50 patients in the early phase, in which tranexamic acid was not employed, to group N, and 50 in
the late phase, in which tranexamic acid was employed,
to group T. There were no signiﬁcant diﬀerences in any
preoperative factors between the 2 groups (Table 1).
Under general anesthesia, a median sternotomy was
performed. The internal thoracic artery was harvested
and fully skeletonized using a harmonic scalpel.
After graft preparation, heparin was administered

Department of Cardiovascular Surgery, Toyohashi Heart Center,
Toyohashi, Japan
Corresponding author:
Masakazu Aoki, MD, Department of Cardiovascular Surgery, Toyohashi
Heart Center, 21-1 Gobutori, Oyama-cho, Toyohashi 441-8530, Japan.
Email: aoki@heart-center.or.jp

Aoki et al.

659

Table 1. Preoperative data in 100 patients undergoing off-pumpcoronary artery bypass.

Table 2. Operative data in 100 patients undergoing off-pumpcoronary artery bypass.

VariableGroup NGroup T

VariableGroup NGroup Tp value

No. of patientsAge (years)
Sex (male/female)
Body mass index (kgm 2)
Chronic kidney disease
Emergency surgery
Ejection fraction
Hematocrit
Antiplatelet agents

50
67  943/7
23  315
1052%  1636%  5%31

50
67  1041/9
24  315
1057%  1137%  5%31

Operation time (min)No. of coronary anastomoses
Internal thoracic artery grafts

276  52
3.4  1
1.8  0.1

278  59
3.5  1
1.9  0.1

0.86860.69030.7805p value

0.83230.58730.37410.789
0.3254

Group N: no tranexamic acid; group T: tranexamic acid before sternal
closure.

systemically so that the activated clotting time was
400 sec or more, and graft anastomosis was conducted.
After completion of the anastomoses, protamine wasadministered to ensure hemostasis. The pericardial
cavity was loosely closed by drawing up the peripheral
fat or pericardium. Silicon drains (28F) were inserted
into the pericardial cavity and mediastinum. The sternum was wired, washed with 2000 mL of warm physiological saline, and closed. In group T, 1 g of tranexamic
acid in 10 mL was sprayed into the pericardial cavity
and mediastinum immediately before the sternum wasclosed. The drain was clamped for approximately
10 min until wound closure, so that the tranexamic
acid penetrated suﬃciently. On completion of surgery,the drain was opened. We compared the volume of
postoperative blood loss, blood transfusion volume,and complications between the 2 groups. Patientswith a serum creatinine level of 1.3 mgdL 1 or more
before surgery were regarded as having chronic renal
failure. Concerning postoperative blood transfusion,concentrated erythrocytes were employed in patientswith a hematocrit value of 25% or less. Fresh frozen
plasma and concentrated platelets were selected basedon the attending physician’s evaluation. Patients with aserum creatinine level of 1.5 mgdL 1 or more on discharge or an increase of 0.5 mgdL 1 or more comparedto the pretreatment value were regarded as having
kidney dysfunction.
Statistical analysis was conducted using the chisquared and Student’s t tests. A p value <0.05 wasregarded as signiﬁcant.

Group N: no tranexamic acid; group T: tranexamic acid before sternal
closure.

Table 3. Postoperative data in 100 patients undergoing
off-pump coronary artery bypass.
VariableGroup N24-h blood loss (mL)
Blood transfusion (units)
Red cells
Fresh-frozen plasma
Platelets
Intubation time (h)Reexploration
Atrial fibrillation
Sternal infection
Renal failure
SeizureStrokeMyocardial infarction
Graft patency
Intensive care unit stay (days)
Hospital death492  180 303  112 <0.0001
105014.2  8.4
0
13
4
1
0
0
0
97.3%
1.0  0.3
0Group T5
1
0
12.8  7.1
0
11
0
0
0
2
1
94.2%
1.0  0.1
0p value

0.23370.45920.23370.41810.64130.04230.31730.15520.31730.92780.4130Group N: no tranexamic acid; group T: tranexamic acid before sternal
closure.

internal thoracic artery grafts (Table 2). Postoperative
factors are presented in Table 3. The volume of blood
loss in the ﬁrst 24 h after intensive care unit admission
was 492  180 mL in group N and 303  112 mL ingroup T (p < 0.0001); the latter showed a signiﬁcantdecrease of approximately 40% (Figure 1). There wasno signiﬁcant diﬀerence in the blood transfusion
volume. There were also no signiﬁcant diﬀerences in
the incidences of kidney dysfunction, convulsion, cerebral infarction, postoperative myocardial infarction,
graft patency rate, or intensive care unit stay between
the 2 groups. There was no death during admission ineither group.

Results
There were no signiﬁcant diﬀerences in intraoperative
factors between the 2 groups, with respect to operation
time, number of coronary anastomoses, or number ofDiscussion
Since the introduction of OPCAB, the incidenceof postoperative hemorrhage has decreased, with

660

Figure 1. Volume of blood loss in 50 patients who received
local tranexamic acid (group T) and 50 controls (group N).

reductions in the dose of heparin administered during
surgery and pericardial operations, minimizing thenecessity for blood transfusion and additional thoracotomy.8 However, surgery is becoming indicated for
an increasing number of patients due to the low degreeof invasiveness of OPCAB; the number of elderly andhigh-risk patients with a high incidence of complications, in whom surgery was not selected previously,
has increased. In addition, the number of patientswith the risk of hemorrhage may also be increasing.
A study reported that risk factors for postoperative
hemorrhage, blood transfusion, and reexploration
included age 75 years or older, renal failure, anemia,
emergency surgery, body mass index <25 kgm 2, andoral administration of antiplatelet agents.9 In thisstudy, patients aged 75 years or older accounted for
25%. Renal failure was noted in 30% of patients, andanemia in 33%. Emergency surgery was performed in
20%, and the body mass index was less than 25 kgm 2
in 75%; 96% had 1 or more risk factors. Furthermore,
62% of our patients had received antiplatelet agents
until the day before surgery.
A previous study indicated the involvement of theﬁbrinolytic system in 25% to 45% of patients withpostoperative hemorrhage.10 In the 1980s, local administration of antiﬁbrinolytic agents was introduced as aneﬀective method of administration with a low incidenceof side eﬀects in the ﬁelds of oral surgery, neurosurgery,otorhinolaryngology, urology, obstetrics and gynecology. Several studies have reported the hemostaticeﬀects and safety of antiﬁbrinolytic agents.11 In theﬁeld of cardiac surgery, Tatar and colleagues4 locallyadministered aprotinin into the pericardial cavity forthe ﬁrst time in 1993. Since the withdrawal of aprotinin,
many studies have reported the local administration oftranexamic acid and epsilon aminocaproic acid.5–7
However, these studies involved patients who had surgery under cardiopulmonary bypass. No study hasreported local administration of antiﬁbrinolytic agentsto OPCAB patients.

Asian Cardiovascular & Thoracic Annals 20(6)In this study, we locally administered tranexamic
acid to OPCAB patients, which is inexpensive and exhibits the most marked hemostatic eﬀects among antiﬁbrinolytic agents;11 there was an approximately 40%
decrease in blood loss in the ﬁrst 24 h after surgery.
Tranexamic acid inhibits ﬁbrin adsorption by binding
to plasminogen, producing antiﬁbrinolytic actions.12
This agent is known to show antiinﬂammatory andantiallergic actions in addition to hemostatic eﬀects.
It has been added to dental paste to achieve gingival
hemostasis and reduce inﬂammation, and is commonly
employed for local administration.13 The mechanism ofaction of locally administered tranexamic acid remains
to be clariﬁed, but several studies have indicated that it
reduces postoperative hemorrhage.5–7 Tissue plasminogen activator is secreted by mesothelial cells to physiologically prevent adhesion in vivo. In the pericardial
cavity, a similar function also acts to prevent adhesion
and maintain ﬂow ability.14 In addition, during open
heart surgery, trauma may further enhance the activityof the ﬁbrinolytic system.15 Philipe and colleagues16
reported that many ﬁbrinolytic factors including plasminogen were present in the pericardial cavity after
open heart surgery, and that the activity of the ﬁbrinolytic system was enhanced. In the pericardial cavity
after open heart surgery, surgical invasion activates
the ﬁbrinolytic system in addition to tissue plasminogenactivator secretion mediated by a physiological adhesion-preventing mechanism; therefore, coagulation andﬁbrinolysis are repeated in response to oozing at thecapillary level. This may be related to changes inpostoperative hemorrhage. The local administrationof antiﬁbrinolytic agents may inhibit the repeated coagulation-ﬁbrinolysis cycle, reducing hemorrhage.
Fibrinolytic factors in the pericardial cavity may also
diﬀuse into the mediastinum due to heart beat, exhibiting the ﬁbrinolytic eﬀects demonstrated in the pericardial cavity. The local administration of tranexamic acidmay decrease the volume of postoperative blood loss by
reducing the activity of the ﬁbrinolytic system in boththe pericardial cavity and mediastinum, and inhibitingﬁbrin decomposition.
In this study, there was no drain occlusion ordelayed cardiac tamponade early after surgery. Local
administration may prevent additional hemorrhage byinhibiting thrombolysis at the aﬀected capillary site,rather than strong thrombus formation from blood in
the pericardial cavity and mediastinum, thus decreasing
the volume of blood loss. According to Isgro and colleagues17 who compared the blood loss volumes
between systematic and local administration of aprotinin in coronary artery bypass patients on heart-lungmachines, there was no signiﬁcant diﬀerence in blood
loss at 24 h after the operation. In addition, they recognized that local administration of aprotinin had an

Aoki et al.
advantage, considering the side eﬀects caused by systematic administration, such as vein bypass occlusion,
myocardial infarction, renal failure, and membrane stabilization eﬀects on platelets. We could not compare
our study because there is no research regarding thesystematical administration of tranexamic acid in
OPCAB patients. Aprotinin is a similar antiﬁbrinolytic
agent to tranexamic acid, thus it would be expected thattranexamic acid has similar eﬀects. The systematic
administration of tranexamic acid has similar side
eﬀects to those of aprotinin.18 We recommend local
administration in OPCAB patients for safety reasons
if both tranexamic acid administration methods havethe same hemostatic eﬀects.
We found no marked diﬀerence in the postoperative
blood transfusion volume between the 2 groups. In contrast, a study by Abul-Azm and Abdullah5 reported
that local administration of tranexamic acid decreased
the postoperative blood transfusion volume. Theirstudy involved coronary artery bypass in patients on
cardiopulmonary bypass, and the volume of postoperative blood loss in the control and tranexamic acid-treated groups was 1208 and 733 mL, respectively. These
values are more than twice as high as those in ourstudy (492  180 vs. 303  112 mL). There was no diﬀerence in the postoperative blood transfusion volumes
between the 2 groups, possibly because only a small
number of patients met the criterion for blood transfusion in our hospital (hematocrit of 25% or less).
Furthermore, no signiﬁcant diﬀerences have beenfound in the incidences of complications such as atrial
ﬁbrillation, renal failure, embolism, or spasm after intravenous administration of tranexamic acid.18 Kolettis
and colleagues19 conducted an animal experiment thatindicated that intrapericardial drug absorption wasrestricted. Considering that the half-life of tranexamic
acid ranges from 1 to 1.5 h, the side eﬀects observed after
intravenous administration may not occur. However, a
study suggested involvement of the ﬁbrinolysis system inadhesion and peritonitis after laparotomy.20 The local
administration of tranexamic acid might cause enhancement of intrapericardial adhesion or pericarditis in thelate phase, hence close follow-up is needed.
As we did not employ a double-blind method in thisstudy, there may have been a bias in hemostatic procedures among surgeons responsible for sternal closure.
However, there was no signiﬁcant diﬀerence in theoperation time between the 2 groups. Therefore, there
may have been no marked diﬀerence in hemostasis.
We concluded that local administration of tranexamic
acid is simple, inexpensive, and safe. In the future, thisprocedure may be applied in other ﬁelds of cardiovascular surgery, and another action of tranexamic acid,an antiinﬂammatory eﬀect in local areas, should be
investigated.

661
Funding
This research received no speciﬁc grant from any funding
agency in the public, commercial, or not-for-proﬁt sectors.

Conflicts of interest statement
None declared.
Presented at the 19th Annual Meeting of the Asian Society for
Cardiovascular and Thoracic Surgery, Phuket, Thailand, May
25–28, 2011.

References
1. Hall TS, Brevetti GR, Skoultchi AJ, Sines JC, Gregory P
and Spotnitz AJ. Re-exploration for hemorrhage following open heart surgery differentiation on the causes of
bleeding and the impact on patient outcomes. Ann
Thorac Cardiovasc Surg 2001; 7: 352–357.
2. Brown RS, Thwaites BK and Mongan PD. Tranexamic
acid is effective in decreasing postoperative bleeding andtransfusions in primary coronary artery bypass operations: a double-blind, randomized, placebo-controlled
trial. Anesth Analg 1997; 85: 963–970.
3. Fergusson DA, Hébert PC, Mazer CD, Fremes S,
MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.
N Engl J Med 2008; 358: 2319–2331.
4. Tatar H, Ciçek S, Demirkiliç U, Ozal E, Süer H, Oztürk
O, et al. Topical use of aprotinin in open heart operations. Ann Thorac Surg 1993; 55: 659–661.
5. Abul-Azm A and Abdullah KM. Effect of topical tranexamic acid in open heart surgery. Eur J Anaesthesiol
2006; 23: 380–384.
6. Breda JR, Gurian DB, Breda AS, Meneghine A, Freitas
AC, Matos LL, et al. Topical use of antifibrinolytic agent
to reduce postoperative bleeding after coronary artery
bypass surgery. Rev Bras Cir Cardiovasc 2009; 24:
341–345.
7. Fawzy H, Elmistekawy E, Bonneau D, Latter D and
Errett L. Can local application of Tranexamic acid
reduce post-coronary bypass surgery blood loss? A randomized controlled trial. J Cardiothorac Surg 2009; 4: 25.
8. Nader ND, Khadra WZ, Reich NT, Bacon DR, Salerno
TA and Panos AL. Blood product use in cardiac revascularization: comparison of on- and off-pump techniques. Ann Thorac Surg 1999; 68: 1640–1643.
9. Vuylsteke A, Pagel C, Gerrard C, Reddy B, Nashef S,
Aldam P, et al. The Papworth Bleeding Risk Score: astratification scheme for identifying cardiac surgery
patients at risk of excessive early postoperative bleeding.
Eur J Cardiothorac Surg 2011; 39: 924–930.
10. Kevy SV, Glickman RM, Bernhard WF, Diamond LK
and Gross RE. The pathogenesis and control of the hemorrhagic defect in open heart surgery. Surg Gynecol
Obstet 1966; 123: 313–318.
11. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985; 29: 236–261.
12. Longstaff C. Studies on the mechanisms of action of
aprotinin and tranexamic acid as plasmin inhibitors and662
antifibrinolytic agents. Blood Coagul Fibrinolysis 1994; 5:
537–542.
13. Ikeda K, Hikima T, Kusunoki K, Watanabe Y, Fujihashi
H, Hiyoshi K, et al. A study of clinical effects of dentifrice including tranexamic acid. Nippon Shishubyo Gakkai
Kaishi 1981; 23: 437–450.
14. Tabuchi N, de Haan J, Boonstra PW and van Oeveren
W. Activation of fibrinolysis in the pericardial cavity
during cardiopulmonary bypass. J Thorac Cardiovasc
Surg 1993; 106: 828–833.
15. Jares M, Vanek T, Bednar F, Maly M, Snircova J andStraka Z. Off-pump versus on-pump coronary artery surgery. Int Heart J 2007; 48: 57–67.
16. Khalil PN, Ismail M, Kalmar P, von Knobelsdorff G andMarx G. Activation of fibrinolysis in the pericardial

Asian Cardiovascular & Thoracic Annals 20(6)cavity after cardiopulmonary bypass. Thromb Haemost
2004; 92: 568–574.
17. Isgro F, Stanisch O, Kiessling AH, Gürler S, Hellstern P
and Saggau W. Topical application of aprotinin in cardiac surgery. Perfusion 2002; 17: 347–351.
18. Martin K, Wiesner G, Breuer T, Lange R and Tassani P.
The risks of aprotinin and tranexamic acid in cardiac
surgery: a one-year follow-up of 1188 consecutive
patients. Anesth Analg 2008; 107: 1783–1790.
19. Kolettis TM, Kazakos N, Katsouras CS, Niokou D,
Pappa L, Koulouras V, et al. Intrapericardial drug delivery: pharmacologic properties and long-term safety inswine. Int J Cardiol 2005; 99: 415–421.
20. Holmdahl L. The role of fibrinolysis in adhesion formation. Eur J Surg Suppl 1997; 577: 24–31.