Tian et al.

Perioperative Medicine (2024) 13:58 Perioperative Medicine

https://doi.org/10.1186/s13741-024-00418-3

REVIEW Open Access

Hemostatic effects of tranexamic acid

in cardiac surgical patients with antiplatelet
therapy: a systematic review and meta‑analysis
Lijuan Tian1, Xiaotao Li2, Lixian He2, Hongwen Ji1, Yuntai Yao1* and the Evidence in Cardiovascular Anesthesia
(EICA) Group

Abstract
Background The purpose of the current study was to assess the efficacy of tranexamic acid (TXA) on reducing
bleeding in cardiac surgical patients with preoperative antiplatelet therapy (APT).
Methods Five electronic databases were searched systematically for randomized-controlled trials (RCTs) assess-
ing the impact of intravenous TXA on post-operative bleeding on cardiac surgical patients with preoperative APT
until May 2024. Primary outcome of interest was post-operative blood loss. Secondary outcomes of interest included
the incidence of reoperation due to post-operative bleeding, post-operative transfusion requirements of red blood
cells (RBC), fresh-frozen plasma (FFP), and platelet concentrates. Mean difference (MD) with 95% confidence interval
(CI) or odds ratios (OR) with 95% CI was employed to analyze the data. Subgroup and meta-regression analyses were
performed to assess the possible influence of TXA administration on reducing bleeding and transfusion requirements.
Results A total of 12 RCTs with 3018 adult cardiac surgical patients (TXA group, 1510 patients; Control group, 1508
patients) were included. The current study demonstrated that TXA significantly reduced post-operative blood loss
(MD =  − 0.38 L, 95% CI: − 0.73 to − 0.03, P = 0.03; MD =  − 0.26 L, 95% CI: − 0.28 to − 0.24, P < 0.00001; MD =  − 0.37 L, 95%
CI: − 0.63 to − 0.10, P = 0.007) in patients receiving dual antiplatelet therapy (DAPT), aspirin, or clopidogrel, respectively.
Patients in TXA group had significantly lower incidence of reoperation for bleeding as compared to those in Control
group. The post-operative transfusion of RBC and FFP requirements was significantly lower in TXA group than Con-
trol group. Subgroup analyses showed that studies with DAPT discontinued on the day of surgery significantly
increased the risk of post-operative blood loss [(MD: − 1.23 L; 95% CI: − 1.42 to − 1.04) vs. (MD: − 0.16 L; 95% CI: − 0.27
to − 0.05); P < 0.00001 for subgroup difference] and RBC transfusion [(MD: − 3.90 units; 95% CI: − 4.75 to − 3.05) vs.
(MD: − 1.03 units; 95% CI: − 1.96 to − 0.10); P < 0.00001 for subgroup difference] than those with DAPT discontinued
less than 5–7 days preoperatively.
Conclusions This meta-analysis demonstrated that TXA significantly reduced post-operative blood loss and transfu-
sion requirements for cardiac surgical patients with preoperative APT. These potential clinical benefits may be greater
in patients with aspirin and clopidogrel continued closer to the day of surgery.
Trial registration number CRD42022309427.
Keywords Tranexamic acid, Cardiac surgery, Antiplatelet therapy, Post-operative bleeding

*Correspondence:
Yuntai Yao
[email protected]
Full list of author information is available at the end of the article

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Tian et al. Perioperative Medicine (2024) 13:58 Page 2 of 14

Introduction loss volume in patients undergoing major operations

Post-operative bleeding is a common and crucial clini- (Amour et al. 2016).
cal consequence of cardiac surgery with complex and The purpose of the present study was to evaluate the
multifactorial causes including procedures, patient char- blood-saving effects of TXA administration on adult car-
acteristics, and medications (Paparella et al. 2004; Mur- diac surgical patients with preoperative APT.
phy et al. 2007). Most patients diagnosed with coronary
artery disease receive preoperative dual antiplatelet ther- Methods
apy (DAPT) with aspirin and ­P2Y12 inhibitors to prevent Ethics
occurrence of thrombotic events before cardiac surgery According to the Ethical Committee of Fuwai Hospital,
(Janssen et al. 2017). In elective surgery, discontinua- ethics approval was not required for meta-analysis. The
tion of antiplatelet therapy (APT) should be individually protocol of current meta-analysis has been registered on
adjusted according to the consensus of anesthesiologists, the International Prospective Systematic Reviews Regis-
surgeons, and patients to minimize ischemic risks and try database (CRD42022309427).
bleeding risks during surgery. Platelet dysfunction is one
of the most common reasons for post-operative massive Patient and public involvement
bleeding in cardiac surgical patients (Berger et al. 2012; Patients and/or the public did not participate in the
Kremke et al. 2013). A national registry report from Swe- design, or execute, or statement, or dissemination of this
den and a single-center study have demonstrated that study.
transfusion of blood products was greater in patients
with APT before coronary artery bypass grafting (CABG) Search strategy
surgery, and about 3.9% of mortality occurred in patients We conducted a systemic review according to Preferred
treated with clopidogrel (Tomšič et al. 2016; Hansson Reporting Items for Systematic Reviews and Meta-Anal-
et al. 2016). To improve clinical prognosis, prevention ysis Guidelines (PRIMSA) (Higgins et al. 2020) (Sup-
of perioperative blood loss may be more effective than plemental Table 1, PRISMA Checklist). PubMed, Ovid,
reducing allogeneic blood transfusions (Biancari et al. Embase, the Cochrane Central Register of Controlled
2018). For patients at risk of bleeding, the current clini- Trials (CENTRAL), and China National Knowledge
cal practice guidelines strongly recommend the admin- Infrastructure (CNKI) database (until May 2024) were
istration of antifibrinolytic agents to reduce blood loss systematically searched to all RCTs assessing the impact
and blood transfusion during cardiac surgery and blood of intravenous TXA administration on post-operative
conservation, based largely on results of large-scale clini- bleeding and allogeneic blood products for adult cardiac
cal studies (Tibi et al. 2021; Pagano et al. 2018). Since surgical patients with preoperative APT. The searching
aprotinin was withdrawn from the market, tranexamic keywords used were as follows: (cardiac surgery OR coro-
acid (TXA) has become the most popular antifibrino- nary artery bypass surgery OR cardiovascular surgery OR
lytic agent and provided effective benefit in antiplatelet- operation OR procedure) AND (aspirin OR clopidogrel
associated bleeding in cardiac surgery without significant OR antiplatelet OR single antiplatelet therapy OR dual
thromboembolic events (Fischer et al. 2020a). antiplatelet therapy OR SAPT OR DAPT OR acetylsali-
The effectiveness and efficacy of TXA on patients cylic acid OR ticagrelor) AND (tranexamic acid) AND
with impaired platelet dysfunction remain undeter- (randomized controlled trial OR controlled clinical trial
mined. Previous studies suggested that TXA adminis- OR randomized OR placebo OR randomly OR trial).
tration could improve platelet function via inhibition Detailed search strategies were reported in Supplemen-
of plasminogen to plasmin conversion (Pabinger et al. tal Table 2. No language restriction was applied. To make
2017; Mahla et al. 2018). Several studies have provided sure that all relevant articles were included, references
preliminary evidence that TXA could promote platelet of highlighted research were thoroughly searched. Two
function in patients undergoing CABG with APT and authors (L. J. T. and Y. T. Y.) independently reviewed
reduce post-operative bleeding and the incidence of allo- all the retrieved records by reading the titles, abstracts,
geneic blood transfusion (Weber et al. 2011; Pleym et al. and keywords in a non-blind, standardized manner to
2003). A prior review indicated that TXA administration determine which studies met the inclusion criteria and
was associated with a reduced risk of bleeding follow- removed those ineligible ones. The eligibility studies ulti-
ing either single antiplatelet treatment (SAPT) or DAPT mately included in the analysis were further determined
by improving platelet function (Fischer et al. 2020b). by evaluating the full text. Any discrepancy was resolved
Another recently published trial demonstrated that TXA through discussion, and other reviewers (X. T. L. and L.
administration was not associated with reduced blood X. H.) participated to resolve conflicts.
Tian et al. Perioperative Medicine (2024) 13:58 Page 3 of 14

Inclusion and exclusion criteria STATA 12.0 (Stata Corp., College Station, TX, USA).
The inclusion criteria were as follows: (1) adult cardiac Continuous variables and treatment effect were pre-
surgical patients with preoperative APT, (2) intraopera- sented as mean difference (MD) with 95% confidence
tive intravenous TXA administration versus placebo or interval (CI). Dichotomous variables analyzed with
blank, (3) randomized controlled trials (RCTs), and (4) odds ratio (OR) with 95% CI. Additionally, the formulas
at least one of the predetermined outcomes listed in the of (Wan et al. 2014) transformed continuous variables
following reported. Primary outcomes were post-opera- that were described as median and interquartile range
tive blood loss. Secondary outcomes were the incidence (IQR) into mean and standard deviation (SD). The
of reoperation due to post-operative bleeding, post- random-effect model was used to pool the data for the
operative transfusion of red blood cells (RBC), fresh- consideration of methodological and clinical heteroge-
frozen plasma (FFP) and platelet concentrates (PC), and neity (I2 > 50% or P < 0.05), and the fixed-effect model
post-operative recovery including mechanical ventila- was used for analysis that there was no significant het-
tion duration (MVD), and post-operative length of stay erogeneity. Statistical heterogeneity among studies was
(LOS) in the intensive care unit and hospital. assessed using the Q test and I2 statistics. According
Exclusion criteria included the following: (1) studies pub- to the Cochrane Handbook, the percentages of I2 at
lished as review articles, case reports, expert experience, 0–25%, 25–50%, and 75–100% indicate low, medium,
or abstracts, (2) retrospective or observational studies, (3) and high heterogeneity, respectively. After statistical
studies based on animal models, (4) outcomes of interest heterogeneity is established, the researchers searched
could not be extracted and analyzed, (5) duplicate publica- for possible sources from the clinical and methodo-
tions, and (6) aminocaproic acid or aprotinin as control. logical perspective and then perform subgroup or
sensitivity analysis to detect the possible causes of het-
Study quality assessment erogeneity. The sensitivity analysis was performed to
Two investigators (L. J. T. and Y. T. Y.) independently evaluate the influence of individual study on the over-
assessed the risk of bias by using the tool described in the all estimate by omitting each study in turn. Subgroup
Cochrane Handbook for Systematic Reviews of Interven- and meta-regression analyses were performed to detect
tions (Higgins et al. 2011). The quality of the study was the possible sources of inconsistency and heterogene-
categorized as low risk if there is no indication of risk ity. Meta-regression was conducted with the following
of bias, medium risk if there is a potential risk of bias, covariates: (I) SAPT and DAPT and (II) TXA regimens.
or high risk if there is a clear indication of risk of bias. Subgroup analysis was employed to investigate the
Additionally, L. J. T. and Y. T. Y. independently evaluated association between different DAPT discontinued
the methodologic quality of each included trial using the time and surgical technology and clinical outcomes
modified Jadad score (Jadad et al. 1996). Modified Jadad (post-operative bleeding and allogeneic blood transfu-
quality scoring scale included the generation of random sion). Publication biases were examined with the Begg’s
sequences, randomized concealment, and whether blind test and visualized the symmetry of the funnel plots
method and reporting the withdrawals was adopted. For of the outcomes (Egger et al. 1997). All P-values were
each item, there were associated criteria and scores, with two sided, and statistical significance was defined as
less than or equal to 3 points as low-quality research and P < 0.05.
4–7 points as high-quality research.

Data abstraction Results

General information, participants characteristics, inter- Literature search, study characteristics, and quality
vention, and follow-up data for eligible study were inde- assessment
pendently extracted by two investigators L. J. T. and As shown in the flowchart (Fig. 1), 418 records were
Y. T. Y. and included research title, first author, year of initially identified in the databases. A total of 392 tri-
publication, journal, country, number of patients, gen- als were excluded due to duplication and review of
der, age, type of surgical procedure, and data regard- titles and abstracts. Finally, 12 (Pleym et al. 2003; Ahn
ing outcomes of interest. Discrepancies were discussed et al. 2012; Shi et al. 2013a, 2013b, 2013c; Altun et al.
among all authors at the end of assessment. 2017; Banihashem et al. 2019; Khadanga et al. 2020;
Landymore et al. 1997; Guo et al. 2007; Aelbrouck et al.
2016; Myles et al. 2017) eligible trials that satisfied the
Statistical analysis
inclusion criteria were included in this meta-analysis.
Statistical analyses were performed using Review Man-
Descriptive analyses of these articles were presented in
ager 5.4 (Cochrane Collaboration, Oxford, UK) and
Tian et al. Perioperative Medicine (2024) 13:58 Page 4 of 14

Fig. 1 Flowchart of the study search and selection process

Table 1. Of the 12 eligible trials, 2 (Shi et al. 2013b; Guo included participants undergoing on-pump CABG,
et al. 2007) were written in Chinese, the other 10 (Pleym three trials (Ahn et al. 2012; Khadanga et al. 2020; Guo
et al. 2003; Ahn et al. 2012; Shi et al. 2013a, 2013c; et al. 2007) included off-pump CABG patients, and two
Altun et al. 2017; Banihashem et al. 2019; Khadanga trials (Aelbrouck et al. 2016; Myles et al. 2017) included
et al. 2020; Landymore et al. 1997; Aelbrouck et al. 2016; mixed cardiac surgical patients.
Myles et al. 2017) were in English (1 (Ahn et al. 2012)
from Korea, 2 (Shi et al. 2013a, 2013c) from China, 1 Study patient and intervention characteristics
(Altun et al. 2017) from Turkey, 1 (Banihashem et al. The characteristics of the 12 RCTs are presented in Table 1.
2019) from Iran, 1 (Khadanga et al. 2020) from India, The screening included 3018 patients undergoing cardiac
1 (Landymore et al. 1997) from Canada, 1 (Pleym et al. surgery, and 1510 were assigned to TXA group and 1508
2003) from Norway, 1 (Aelbrouck et al. 2016) performed to Control group. Eleven trials compared TXA with saline
in Belgium and USA, 1 (Myles et al. 2017) performed (Pleym et al. 2003; Ahn et al. 2012; Shi et al. 2013a, 2013b,
in Australia, Canada, Italy, the Netherlands, New Zea- 2013c; Altun et al. 2017; Banihashem et al. 2019; Khadanga
land, China (Hong Kong), and UK). Seven trials (Pleym et al. 2020; Guo et al. 2007; Aelbrouck et al. 2016; Myles
et al. 2003; Shi et al. 2013a, 2013b, 2013c; Altun et al. et al. 2017), and 1 trial compared TXA with blank (Land-
2017; Banihashem et al. 2019; Landymore et al. 1997) ymore et al. 1997). Six trials (511 patients), 5 trials (2379
Table 1 Characteristics of included studies
Author, year Country Surgery Sample size Group TXA group Control group Antiplatelet Outcome
medication

(Ahn et al. 2012) Korea OPCAB 76 2 TXA (n = 38): 1 g Saline (n = 38) Stop clopidogrel ①, ②, ③, ④, ⑧
before SI, 200 mg/h and aspirin
until OP end less than 5 days preop-
eratively
Tian et al. Perioperative Medicine

(Shi et al. 2013a) (1) China On-pump CABG 117 2 TXA (n = 58): 15 mg/ Saline (n = 59) Stop clopidogrel ①, ②, ③, ④,
kg before SI, 15 mg/kg and aspirin ⑤, ⑥, ⑦, ⑧
after protamine neutrali- less than 7 days preop-
zation eratively
(Shi et al. 2013b) (2) China On-pump CABG 110 2 TXA (n = 55): 10 mg/kg Saline (n = 55) Stop clopidogrel ①, ②, ③, ④,
after induction, 10 mg/ and aspirin ⑤, ⑥, ⑦, ⑧
(2024) 13:58

kg/h until OP end less than 7 days preop-

eratively
(Altun et al. 2017) Turkey On-pump CABG 54 4 TXA (n = 18): 10 mg/ ①Blank (n = 10): No Stop clopidogrel ①, ②, ③, ④,
kg before SI, continued drug and aspirin until the day ⑤, ⑥, ⑦
1 mg/kg/h for 10 h ②TXA + Des (n = 16): of surgery
10 mg/kg before SI,
1 mg/kg/h for 10 h, Des
0.3 µg/kg after prota-
mine neutralization
③Des (n = 10): 0.3 µg/
kg after protamine
neutralization
(Banihashem et al. 2019) Iran On-pump CABG 120 2 TXA (n = 60): 10 mg/ Saline (n = 60) Stop clopidogrel ①, ②, ④, ⑤, ⑥
kg before SI, 10 mg/kg and aspirin
after protamine neutrali- less than 5 days preop-
zation eratively
(Khadanga et al. 2020) India OPCAB 60 2 TXA (n = 30): 10 mg/kg Saline (n = 30) Stop clopidogrel 5 days ①, ⑤, ⑥, ⑦, ⑧
after induction preoperatively, aspirin
until the day of surgery
(Landymore et al. 1997) Canada On-pump CABG 198 4 TXA (n = 56): 10 mg/kg ①Blank (n = 50): No Stop aspirin 48 h preop- ①
before CPB, continued drug eratively
1 mg/kg/h during CPB ②Aprotinin (n = 48):
20 × ­104 KIU before CPB,
20 × ­104 KIU /h dur-
ing CPB
③EACA (n = 44): 5 g
before CPB, 1 g/h dur-
ing CPB
(Pleym et al. 2003) Norway On-pump CABG 79 2 TXA (n = 40): 30 mg/kg Saline (n = 39) Stop aspirin ①, ②, ③, ④, ⑧
before CPB until the day of surgery
(Guo et al. 2007) China OPCAB 112 3 TXA (n = 36): 0.75 g ①Saline (n = 40) Stop aspirin 5–7 days ①, ②, ③
before SI, 0.25 g/h ②Aprotinin (n = 36): preoperatively
until OP end 10 × ­105 KIU before SI,
5
5 × ­10 KIU/h until OP end
Page 5 of 14
Table 1 (continued)
Author, year Country Surgery Sample size Group TXA group Control group Antiplatelet Outcome
medication

(Van Aelbrouck et al. Belgium, USA Cardiac surgery 28 4 ①TXA1 (n = 9): ①Saline1 (n = 9): Stop aspirin ①, ②, ③, ④
2016) Aspirin discontinued Aspirin discontinuation until the day of surgery
before the day of sur- before the day of sur-
gery with TXA 30 mg/kg gery treated with saline
Tian et al. Perioperative Medicine

loading dose followed ②Saline2 (n = 5): No

by 16 mg/kg/h until OP aspirin patients treated
end with saline
②TXA2 (n = 5): No
aspirin patients with TXA
30 mg/kg loading dose
(2024) 13:58

followed by 16 mg/kg/h
until OP end
(Myles et al. 2017) Australian, Canada, OPCAB and on-pump 4662 4 ①TXA1 (n = 1047): ①Saline1 (n = 1053): Stop aspirin ①, ②, ③, ⑧
Italy, Netherlands, New CABG Aspirin discontinua- Aspirin discontinuation until the day of surgery
Zealand, China (Hong tion before the day before the day of sur-
Kong), UK of surgery with TXA gery treated with saline
100 mg/kg or 50 mg/kg ②Saline2 (n = 1267): No
after induction aspirin patients treated
②TXA2 (n = 1264): No with saline
aspirin patients treated
with TXA 100 mg/kg
or 50 mg/kg after induc-
tion
(Shi et al. 2013c) (3) China On-pump CABG 552 6 ①TXA1 (n = 63): Clopi- ①Saline1 (n = 65): Clopi- Stop clopidogrel ①, ②, ③, ④, ⑧
dogrel discontinued dogrel discontinued less than 7 days preop-
within 7 days before sur- within 7 days before sur- eratively
gery with TXA 10 mg/kg gery with saline
after induction, 10 mg/ ②Saline2 (n = 106):
kg/h until OP end Clopidogrel dis-
②TXA2 (n = 105): Clopi- continued for more
dogrel discontinued than 7 days with saline
for more than 7 days ③Saline3 (n = 107): No
with TXA 10 mg/kg clopidogrel patients
after induction, 10 mg/ with saline
kg/h until OP end
③TXA3 (n = 106): No
clopidogrel patients
with TXA 10 mg/kg
after induction, 10 mg/
kg/h until OP end
OPCAB Off-pump coronary artery bypass graft, CABG Coronary artery bypass grafting, TXA Tranexamic acid, SI Skin incision, OP Operation, CPB Cardiopulmonary bypass, Des Desmopressin acetate, EACA​Aminocaproic
acid. Outcomes ①, bleeding; ②, post-operative red blood cell transfusion rate and volume; ③, post-operative fresh-frozen plasma transfusion rate and volume; ④, post-operative platelet concentrates transfusion rate
and volume; ⑤, mechanical ventilation duration; ⑥, lengths of stay in the intensive care unit; ⑦, hospital length of stay; ⑧, reoperation for bleeding
Page 6 of 14
Tian et al. Perioperative Medicine (2024) 13:58 Page 7 of 14

patients), and 1 trial (128 patients) described patients who Effects on post‑operative FFP transfusion
underwent DAPT, aspirin, or clopidogrel therapy, respec- Four trials (4 comparisons, 331 patients) and 1 trial (1
tively. TXA administration regimens (dosage, timing of comparison, 128 patients) reported post-operative FFP
administration, and route) were not uniform due to dif- transfusion volume in patients with DAPT and clopi-
ferences in the design endpoints of the included trials. The dogrel, respectively (Table 1). TXA significantly reduced
loading dose of TXA ranged from 10 to 100 mg/kg and post-operative FFP transfusion volume in patients receiv-
maintaining dose from 0 to 16 mg/kg/h, respectively. ing DAPT [(MD =  − 1.60 units; 95% CI: − 3.01 to − 0.19;
P = 0.03) with heterogeneity (I2 = 92%, P < 0.00001)], and
Effects on post‑operative blood loss volume clopidogrel [(MD =  − 2.00 units; 95% CI: − 3.31 to − 0.69;
Six trials (6 comparisons, 511 patients), 3 trials (3 com- P = 0.003) (Fig. 4A). Seven trials with 604 patients described
parisons, 203 patients), and 1 trial (one comparison, 128 post-operative FFP transfusion rate (TXA group, 47.16%
patients) described post-operative blood loss volume in vs. Control group, 64.92%). Meta-analysis demonstrated
patients with DAPT, aspirin, and clopidogrel, respectively that there was a significant reduction in the incidence of
(Table 1). Meta-analysis revealed that TXA significantly post-operative FFP transfusion in patients receiving DAPT
reduced post-operative blood loss volume in patients (OR = 0.27; 95% CI: 0.15 to 0.48; P < 0.0001) without heter-
receiving DAPT [(MD =  − 0.38 L; 95% CI: − 0.73 to − 0.03; ogeneity and clopidogrel (OR = 0.24; 95% CI: 0.10 to 0.56;
P = 0.03) with heterogeneity (I2 = 95%, P < 0.00001)], aspi- P = 0.0009) in TXA group (Fig. 4B).
rin [(MD =  − 0.26 L; 95% CI: − 0.28 to − 0.24; P < 0.00001)
without heterogeneity (I2 = 0%, P < 0.61)], and clopidogrel Effects on post‑operative PC transfusion
(MD =  − 0.37 L; 95% CI: − 0.63 to − 0.10; P = 0.007) (Fig. 2A). Three trials (3 comparisons, 265 patients) in patients with
DAPT reported post-operative PC transfusion volume in
Effects on reoperation for bleeding patients with DAPT (Table 1). The meta-analysis demon-
Eight trials (2698 patients) reported reoperation for strated that PC transfusion volume was similar between
bleeding with an overall incidence of 2.63% (TXA group, the TXA group and Control group (MD =  − 0.05 units;
1.11% vs Control group, 4.15%) (Table 1). Compared with 95% CI: − 0.52 to 0.42; P = 0.83) without heterogene-
Control group, there was a significant reduction in the ity (Supplemental Fig. 3A). Three trials (3 comparisons,
incidence of reoperation for bleeding in patients receiv- 303 patients) and 2 trials (2 comparisons, 97 patients)
ing DAPT (OR = 0.08; 95% CI: 0.01 to 0.60; P = 0.01) reported post-operative PC transfusion rate in patients
without heterogeneity, aspirin (OR = 0.36; 95% CI: 0.20 with DAPT and aspirin, respectively (Table 1). Meta-
to 0.66; P = 0.001) without heterogeneity, and clopidogrel analysis demonstrated that PC transfusion rate was no
(OR = 0.16; 95% CI: 0.02 to 1.36; P = 0.01) (Fig. 2B). significant different between the two groups (6% vs. 6.5%)
without heterogeneity (Supplemental Fig. 3B).
Effects on post‑operative RBC transfusion
Five trials (5 comparisons, 391 patients), 4 trials (4 com- Effects on post‑operative recovery
parisons, 2361 patients), and 1 trial (1 comparison, 128 The post-operative MVD was explored in 5 trials includ-
patients) described post-operative RBC transfusion vol- ing 435 patients receiving DAPT without statistically
ume in patients with DAPT, aspirin, and clopidogrel, significant difference between the 2 groups (Table 1,
respectively (Table 1). Meta-analysis demonstrated that Supplemental Fig. 4A). The LOS in ICU (5 comparisons,
TXA significantly reduced post-operative RBC transfu- 435 patients) and hospital (4 comparisons, 315 patients)
sion in patients receiving DAPT [(MD =  − 2.05 units; were examined in cardiac surgical patients with DAPT
95% CI: − 3.68 to − 0.41; P = 0.01) with heterogeneity (Table 1). The post-operative LOS in ICU was similar
(I2 = 92%, P < 0.00001)], aspirin [(MD =  − 0.52 units; 95% between the TXA group and Control group (Supplemen-
CI: − 1.36 to 0.32; P = 0.22) with heterogeneity (I2 = 98%, tal Fig. 4B). The length of stay in hospital was comparable
P < 0.00001)], and clopidogrel (MD =  − 4.00 units; 95% to no significant difference between the two groups (Sup-
CI: − 7.08 to − 0.92; P = 0.01) (Fig. 3A). Nine trials with plemental Fig. 4C).
784 patients reported post-operative RBC transfusion
rate (TXA group, 57.33% vs. Control group, 67.85%). Meta‑regression and subgroup analyses for potential
Compared with Control group, there was a significant sources of heterogeneity
reduction in the incidence of post-operative RBC trans- The APT schemes (SAPT or DAPT) and TXA regimens
fusion in patients receiving DAPT (OR = 0.35; 95% CI: (bolus or bolus plus continuous infusion) were included
0.20 to 0.62; P = 0.0003) without heterogeneity and clopi- in the univariate meta-regression analyses for the post-
dogrel (OR = 0.33; 95% CI: 0.12 to 0.85; P = 0.02) (Fig. 3B). operative blood loss volume in all studies. Results from
Tian et al. Perioperative Medicine (2024) 13:58 Page 8 of 14

Fig. 2 Forest plot of A post-operative bleeding volume and B the incidence of reoperation for bleeding

the analysis of 10 studies including 842 patients showed CI: − 0.27 to − 0.05); P < 0.00001 for subgroup difference]
no association of APT schemes (coefficient =  − 1.52, and post-operative RBC transfusion volume [(MD: − 3.90
95% CI: − 4.05 to 1.01; P = 0.20) or TXA regimens (coeffi- units; 95% CI: − 4.75 to − 3.05) vs. (MD: − 1.03 units; 95%
cient =  − 1.23, 95% CI: − 4.79 to 2.33; P = 0.45) with TXA CI: − 1.96 to − 0.10); P < 0.00001 for subgroup difference]
reducing post-operative blood loss. than those with DAPT discontinued less than 5–7 days
Subgroup analyses showed that studies with DAPT dis- preoperatively. There was no significant difference in
continued on the day of surgery significantly increased the risk of increased post-operative blood loss, RBC,
the risk of post-operative blood loss volume [(MD: − 1.23 and FFP transfusion volume for cardiac surgical patients
L; 95% CI: − 1.42 to − 1.04) vs. (MD: − 0.16 L; 95% with CPB or not (Supplemental Table 3).
Tian et al. Perioperative Medicine (2024) 13:58 Page 9 of 14

Fig. 3 Forest plot of A RBC transfusion volume and B transfusion rate

Quality assessment (Pleym et al. 2003; Ahn et al. 2012; Landymore et al. 1997;
Five studies with an unclear risk of bias were due to the Guo et al. 2007; Aelbrouck et al. 2016). Three trials failed
unclear study design in detail for the selective reporting bias to report information on random sequence generation and
Tian et al. Perioperative Medicine (2024) 13:58 Page 10 of 14

Fig. 4 Forest plot of A FFP transfusion volume and B transfusion rate

were rated to have unclear risk of bias for this item (Altun et al. 2007; Aelbrouck et al. 2016; Myles et al. 2017) had
et al. 2017; Landymore et al. 1997; Guo et al. 2007). Two tri- modified Jadad scores ≥ 4 and were considered as high-
als were classified high risk of blinding assessments or par- quality RCTs (Supplemental Table 4).
ticipants and personnel (Altun et al. 2017; Khadanga et al.
2020), one trial was classified high risk of random sequence Sensitivity analyses and publication bias
generation (Banihashem et al. 2019), and the other RCTs Sensitivity analysis was performed by removal of each
were assessed as low bias risk, indicating that they were study to analyze the influence of the overall treatment
of good quality (Supplemental Fig. 1 and Fig. 2). Of the 12 effect on high heterogeneity outcomes (Supplemental
included trials, 9 trials (Pleym et al. 2003; Ahn et al. 2012; Table 5), whereas no contradictory results were found.
Shi et al. 2013a, 2013b, 2013c; Banihashem et al. 2019; Guo For the reduction of post-operative blood loss volume
Tian et al. Perioperative Medicine (2024) 13:58 Page 11 of 14

and FFP transfusion volume in patients receiving DAPT, suggested that TXA administration effectively decreased
heterogeneity changed from high to low by exclusion of post-operative bleeding and reduced the incidence of
two studies conducted from Ahn et al. (patients under- reoperations for bleeding and allogeneic blood transfu-
went OPCAB) (Ahn et al. 2012) and Altun et al. (pre- sion in patients with DAPT preoperatively.
operative DAPT discontinued on the day of surgery) Subgroup analyses showed that studies with DAPT dis-
(Altun et al. 2017). For the reduction of post-operative continued on the day of surgery significantly increased
RBC transfusion volume, heterogeneity changed from 95 the risk of post-operative blood loss volume (MD: − 1.23
to 14% for patients receiving DAPT by exclusion of two L vs. − 0.16 L) and post-operative RBC transfusion vol-
studies conducted from Shi et al. (patients with 15 mg/ ume (MD: − 3.90 units vs. − 1.03 units) than those with
kg TXA after protamine neutralization) (Shi et al. 2013a) DAPT discontinued less than 5–7 days preoperatively.
and Altun et al. (preoperative DAPT discontinued on Preoperative APT schemes are known to cause plate-
the day of surgery) (Altun et al. 2017), and 98% to 0 for let dysfunction and are associated with increased risk of
patients receiving aspirin by exclusion of two studies massive bleeding, blood transfusion, and complications
conducted from Guo et al. (patients underwent OPCAB) (Valgimigli et al. 2018). The Society of Thoracic Surgeon/
(Guo et al. 2007) and Myles et al. (patients underwent Society of Cardiovascular Anesthesiologists guidelines
OPCAB or on-pump CABG) (Myles et al. 2017). No sig- and European Association for Cardio-Thoracic Surgery
nificant publication bias was detected by funnels plot (EACTS)/the European Association of Cardiothoracic
examination with respect to post-operative bleeding vol- Anaesthesiology (EACTA) guidelines have recommend
ume (Supplemental Fig. 5). P-values for the Begg tests that clopidogrel should be discontinued more than
were > 0.05, suggesting a low probability of publication 3 days preceding surgery, and aspirin may be given the
bias. It suggested that there was no obvious publication day before surgery (Society of Thoracic Surgeons Blood
bias in post-operative bleeding volume (Begg’s P = 0.13). Conservation Guideline Task Force et al. 2011; Irving
et al. 2020). The European Society of Cardiology (ESC)
Discussion and the American Heart Association/American College
The current study is the first of its kind to systemically of Cardiology guidelines recommend discontinuation of
determine the efficacy of tranexamic acid on post- clopidogrel for at least 5 days (II A recommendation) to
operative bleeding and transfusion requirements for improve platelet function (Tibi et al. 2021). Despite the
adult cardiac surgical patients with preoperative APT. national/international guidelines or recommendations
TXA administration reduced post-operative bleeding in have documented antiplatelet regimens, the optimal
patients with DAPT or aspirin, RBC, and FFP transfusion perioperative management of patients with APT remains
in patients with DAPT. Furthermore, the incidence of controversial. The decision-making of APT is com-
reoperation for bleeding was significantly lower in TXA plex and should be individually tailored to balance the
group patients who received DAPT or aspirin, compared risk of ischemia/thrombosis and bleeding (Irving et al.
with Control group. These clinical benefits may be more 2020; Tsan et al. 2023). The results of subgroup analyses
significant in patients with DAPT discontinued on the demonstrated that the effectiveness of TXA in reducing
day of surgery. bleeding may be more practical for patients with differ-
The present study was also consistent with the recent ent DAPT discontinued time, especially for those with
systematic review highlighting the effectiveness of TXA shorter withdrawal times. Therefore, further larger multi-
in preventing APT-related bleeding (Fischer et al. 2020b). center RCTs are needed to confirm our conclusions.
The prospective randomized studies (Myles et al. 2017, The present results demonstrated that the incidence of
2019) of patients undergoing CABG surgery with a two- PC transfusion was 6.25%, and there was no significant
by-two factorial design taking aspirin or placebo and difference between the groups. Although PC transfusion
tranexamic acid or placebo conducted by Myles et al. guidelines have been published, the transfusion practices
have revealed that TXA reduced post-operative bleeding were still heterogeneous (Yuan and Otrock 2021). TXA
risk, without increasing the risk of post-operative mortal- prevents the conversion of plasminogen to plasmin and
ity or ischemic complications. In a recent study of 9535 preserves platelet functions (Klein et al. 2022). TXA may
patients undergoing noncardiac surgery, the incidence of affect the interaction between glycoprotein Ib receptors
the composite bleeding outcome was significantly lower and vWF and have positive impact on platelet functions
with TXA than with placebo (Devereaux et al. 2022). A to decrease the risk of bleeding (Mahla et al. 2018). For
large retrospective cohort study including 19,687 patients example, (Weber et al. 2011) proved that TXA adminis-
who underwent off-pump CABG conducted by Wang tration was able to partially reverse platelet aggregation
et al. found that the application of TXA was safe and dysfunction induced by APT. Some other RCTs have also
provided blood protection (Wang et al. 2022). Our result shown the effects of TXA in preventing blood loss in
Tian et al. Perioperative Medicine (2024) 13:58 Page 12 of 14

CABG patients on continuous aspirin therapy; neverthe- outcomes. Different research designs, different methods
less, TXA did not significantly lower the need for blood of parameters collection, criteria for blood transfusion
transfusions compared to control (Pleym et al. 2003; practices, and statistical analysis to determine the qual-
Guo et al. 2007). The pilot research conducted by Van ity of the study could lead to heterogeneity between stud-
Aelbrouck et al. has indicated that TXA treatment dra- ies. Third, only 12 RCTs with comparatively small sample
matically decreased the severity of CPB-induced plate- size were selected for the meta-analysis with respect to
let dysfunction in patients who were aspirin-free with sample size, especially for several parameters, which may
normal preoperative platelet function (Aelbrouck et al. increase the chance of inaccurate conclusion and publi-
2016). However, significant platelet dysfunction caused cation bias. We contacted the corresponding authors for
by preoperative administration of aspirin until the day missing data, but not much reply was received. Some
of surgery was not improved by TXA administration in recent studies have indicated that in a dose-dependent
their study. The results from our meta-regression analy- fashion, TXA was related to an increase of thrombotic
sis of 842 patients did not find a correlation between the complications (Tsan et al. 2023; Guo et al. 2019; Murkin
APT regimen (SAPT or DAPT) and the reduction of et al. 2010). Therefore, the findings of the current study
post-operative blood loss by TXA. The difference in the should be explained with caution. Large-scale rand-
clinical trial designs, including aspirin withdraw time and omized trials are warranted to make a strong recommen-
different methods of parameters collection, may be con- dation for TXA in reversing bleeding related to APT.
tributed to the inconsistency of results.
In our meta-regression, results found that the TXA
regimen (bolus or bolus plus continuous infusion) was Conclusions
not related to the reduction of post-operative blood loss The current study provides some evidence that TXA is
by TXA. The strategy of TXA in cardiac surgery has long effective in reducing post-operative blood loss and alloge-
been a topic of debate. Fibrinolysis was inhibited by more neic blood transfusion for adult cardiac surgical patients
than 90% at plasma concentrations of TXA approxi- receiving preoperative APT. These potential clinical ben-
mately 20 µg/mL (Andersson et al. 1968). Some studies efits may be greater in patients with aspirin, and clopi-
and reviews have found that effective plasma concen- dogrel continued closer to the day of surgery. Further,
trations of TXA required to inhibit fibrinolysis in vitro well-designed randomized trials are needed to confirm
was approximately 10 µg/mL in adults and 5 µg/mL in the effectiveness of TXA in improving platelet function.
children (Picetti et al. 2019; Guo et al. 2019; Rozen et al. Abbreviations
2015; Grassin-Delyle et al. 2018). Another multicenter, APT Antiplatelet therapy
TXA Tranexamic acid
double-blind, RCT published by (Shi et al. 2022), com- CNKI China National Knowledge Infrastructure
paring the efficacy and adverse events of high-dose and RCT​ Randomized-controlled trial
low-dose TXA in cardiac surgical patients with CPB, RBC Red blood cell
FFP Fresh-frozen plasma
has suggested that a high-dose regimen of TXA (30 mg/ PC Platelet concentrates
kg bolus and 16 mg/kg/h maintenance infusion) resulted MVD Mechanical ventilation duration
in a statistically significant reduction in the incidence of LOS Length of stay
MD Mean difference
allogeneic RBC transfusions. TXA administration varied CI Confidence interval
significantly among studies, and there was no consensus OR Odds ratio
on the ideal dosage of TXA, delivery methods (intrave- DAPT Dual antiplatelet treatment
CABG Coronary artery bypass grafting
nous or topical), or continuous infusion/bolus regimen. SAPT Single antiplatelet treatment
Further trials should be conducted to verify the efficacy IQR Interquartile range
and optimal medication regimen of TXA administration SD Standard deviation
CPB Cardiopulmonary bypass
for patients are at high-risk post-operative bleeding due
to APT.
This study has some limitations. First, there were con- Supplementary Information
The online version contains supplementary material available at https://​doi.​
cerns with quality and heterogeneity of included studies, org/​10.​1186/​s13741-​024-​00418-3.
as well as heterogeneity in the various TXA regimens
(e.g., medicine, dosage, route, time of administration), Supplementary Material 1. Supplemental Fig. 1. Risk of bias assessment
different surgical procedures (on-pump or off-pump), summary.
patient comorbidities, outcome definitions, and allo- Supplementary Material 2. Supplemental Fig. 2. Risk of bias assessment
geneic transfusion protocols. Second, meta-analyses graph.

of pooled studies stratified by APT schemes and TXA Supplementary Material 3. Supplemental Fig. 3. Forest plot of (A) platelet
concentration transfusion volume and (B) transfusion rate.
regimens did not eliminate heterogeneity in our study
Tian et al. Perioperative Medicine (2024) 13:58 Page 13 of 14

Amour J, Garnier M, Szymezak J, Le Manach Y, Helley D, Bertil S, et al. Prospec-

Supplementary Material 4. Supplemental Fig. 4. Forest plot of (A) tive observational study of the effect of dual antiplatelet therapy with
mechanical ventilation duration, (B) the length of stay in the intensive care tranexamic acid treatment on platelet function and bleeding after
unit, and (C) length of hospital stay. cardiac surgery. Br J Anaesth. 2016;117(6):749–57.
Supplementary Material 5. Supplemental Fig. 5. Funnels plot examination Andersson L, Nilsoon IM, Colleen S, Granstrand B, Melander B. Role of uroki-
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Banihashem N, Khorasani M, Vaffai H, Naziri F, Khafri S, Seyfi S. The effect of low-
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strategies. Berger JS, Herout PM, Harshaw Q, Steinhubl SR, Frye CB, Becker RC. Bleeding-
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pump coronary artery bypass. J Thromb Thrombolysis. 2012;34(1):56–64.
the potential sources of heterogeneity.
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Supplementary Material 9. Supplemental Table 4. Modified Jadad score of ation in preoperative antithrombotic strategy, severe bleeding, and
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high heterogeneity outcomes. 2018;4(4):246–57.
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and manuscript drafting. LJT, XTL, LXH: Acquisition, analysis, and interpretation antiplatelet use: the role of tranexamic acid. Cureus. 2020b;12(9):e10290.
of the data. HWJ: Formal analysis. All authors were involved in drafting and Grassin-Delyle S, Theusinger OM, Albrecht R, Mueller S, Spahn DR, Urien S, et al.
revision of the manuscript for important intellectual content and approved Optimisation of the dosage of tranexamic acid in trauma patients with
the final version to be published. population pharmacokinetic analysis. Anaesthesia. 2018;73(6):719–29.
Guo J, Gao X, Ma Y, Lv H, Hu W, Zhang S, et al. Different dose regimes and
Funding administration methods of tranexamic acid in cardiac surgery: a meta-
This work was funded by CAMS Innovation Fund for Medical Sciences: analysis of randomized trials. BMC Anesthesiol. 2019;19(1):129.
CIFMS-2021-I2M-C&T-B-038. Guo Z, Jian K, Wei M, Guo Z, Li P, Han J, et al. Tranexamic acid and half
dose aprotinin in off-pump coronary artery bypass. Chin Circ J.
Availability of data and materials 2007;22(6):455–8.
No datasets were generated or analysed during the current study. Hansson EC, Jidéus L, Åberg B, Bjursten H, Dreifaldt M, Holmgren A, et al. Coro-
nary artery bypass grafting-related bleeding complications in patients
treated with ticagrelor or clopidogrel: a nationwide study. Eur Heart J.
Declarations 2016;37(2):189–97.
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The
Ethics approval and consent to participate Cochrane Collaboration’s tool for assessing risk of bias in randomised
Ethical approval was not needed because this is a meta-analysis. trials. BMJ. 2011;343:d5928.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane
Consent for publication Handbook for Systematic Reviews of Interventions version 6.1. (updated
Not applicable. September 2020). Cochrane, 2020. Available from www.​train​ing.​cochr​
ane.​org/​handb​ook.
Competing interests Irving AH, Harris A, Petrie D, Higgins A, Smith J, McQuilten ZK. Impact of
The authors declare no competing interests. patient blood management guidelines on blood transfusions and
patient outcomes during cardiac surgery. J Thorac Cardiovasc Surg.
Author details 2020;160(2):437–45.e20.
1
Department of Anesthesiology, National Center for Cardiovascular Diseases, Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al.
Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Assessing the quality of reports of randomized clinical trials: is blinding
Medical College, Beijing 100037, China. 2 Department of Anesthesiology, Yun- necessary? Control Clin Trials. 1996;17(1):1–12.
nan Fuwai Cardiovascular Hospital, Kunming 650102, China. Janssen PWA, Claassens DMF, Willemsen LM, Bergmeijer TO, Klein P, Ten Berg
JM. Perioperative management of antiplatelet treatment in patients
Received: 24 March 2024 Accepted: 11 June 2024 undergoing isolated coronary artery bypass grafting in Dutch cardiotho-
racic centres. Neth Heart J. 2017;25(9):482–9.
Khadanga P, Kanchi M, Gaur P. Effectiveness of tranexamic acid in reducing
postoperative blood loss in patients undergoing off-pump coronary
artery bypass grafting. Cureus. 2020;12(12):e11924.
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