Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery: ATACAS Trial

Myles PS, Smith JA, Forbes A, et al. N Engl J Med. 2017 Jan; 376(2): 136-148.
Journal Club presented by XXXXXXXXX on XXXXXXXXX
Background and Overview
Background Coronary artery bypass graft (CABG) surgery is one of the first treatment
options for patients with coronary artery disease, with >800,000 operations
done annually around the world.
CABG surgery can often be complicated by excessive bleeding, with a
need for blood transfusion.
Antifibrinolytics, such as tranexamic acid (TXA), are recommended in
patients undergoing on-pump CABG to reduce perioperative blood loss
and transfusion requirements (Level of Evidence: A)
Tranexamic acid is used in these surgeries in doses of 10mg/kg (up to
1000mg) with occasional 30mg/kg loading doses.
There are concerns that tranexamic acid may have prothrombotic and
proconvulsant effects. Seizures have a strong association with stroke after
cardiac surgery.
o Seizures typically occur within 5-8 hours after surgery during a
period of weaning from sedation in the PACU or ICU.
o They are typically generalized tonic-clonic events, persisting
for a few minutes, and with recurrent episodes possible.
Study Primary Outcome: Evaluate the risk of death and thrombotic
Objective complications up to 30 days after surgery among at-risk patients
undergoing coronary-artery surgery and receiving tranexamic acid.
Secondary Endpoints:
o Ischemic Complications (MI, stroke, PE, renal failure)
o Bleeding Complications (blood transfusion < 30 days)
Study With the increased use of tranexamic acid in CABG surgeries and the
Significance concerns for its undesirable prothrombotic and proconvulsant effects, it is
important to fully understand the risks and benefits associated with its use.
By understanding the cause and risk of tranexamic acid-associated
seizures, we can recognize the early warning signs, use anesthetics that
may reduce the incidence and severity of seizures, and lead to better
patient outcomes.
Methods
Study Design Between March 2006 and October 2015 with patients at 31 sites in 7
countries.
Multicenter, randomized, placebo-controlled, double-blind trial with a 2-
by-2 factorial design
o Patients who were scheduled to undergo coronary-artery
surgery and were at increased risk for complications were
randomly assigned to one of four treatment groups
Tranexamic Acid
Aspirin (ASA)
Tranexamic Acid and Aspirin
Placebo
Total of 4,662 patients were enrolled and randomized
o TXA Group: 2,311 underwent surgery; 2,269 were assessed
for the primary outcome
 o Placebo Group: 2,322 underwent surgery; 2,288 were
assessed for the primary outcome
Subject Inclusion Criteria Exclusion Criteria
Selection Men and women, aged > 18, undergoing Poor English language
elective coronary artery surgery comprehension
Patient has any of the following: Clinician preference for
o Age > 70 antifibrinolytic therapy
o LV impairment (EF <40%) Urgent surgery for unstable
o Concomitant valvular or coronary syndromes
aortic surgery Active peptic ulcerations
o Aneurysmectomy Allergy or contraindication to
o Repeated cardiac surgery ASA/TXA
o COPD ASA therapy within 5 days of
surgery
o Renal impairment (SCr >2
or CrCl <45) Warfarin or Plavix therapy
o Obesity within 7 days of surgery or
glycoprotein IIb/IIIa
o Pulmonary HTN antagonists within 24 hours
o PVD of surgery
Thrombocytopenia or any
other known history of
bleeding disorder
Severe renal impairment
(SCr >3.3 or CrCl <25)
Recent hematuria
Thromboembolic disease
Pregnancy
Methods TXA was dosed at 100mg/kg as recommended by the BART Trial. Aimed
to maintain an effective plasma concentration for approximately 6-8 hours
by IV bolus over 10-30 minutes.
o After 1,392 patients had been enrolled, the dose was changed
to 50mg/kg due to potential dose-related seizures being
reported. 50mg/kg is still thought to achieve adequate
antifibrinolysis.
Encouraged blinding, but if research personnel were not available, the
anesthesiologist could prepare the drug. These instances were recorded.
The surgical team and postoperative interviewers were still unaware of
the group assignments
TXA or placebo was given IV more than 30 minutes after induction of
anesthesia.
Guidelines were given on the management of excessive bleeding during
surgery, which included use of heparin and protamine. Open label TXA
was only allowed if clinically significant bleeding persisted after the use of
protamine.
o Protamine 4mg/kg used to reverse heparin at completion of
bypass
ECG was obtained preoperatively; on the first, second, and third days
 after surgery; and at discharge
Blood samples were collected at 12-24 hours and 48-72 hours after
surgery to assess troponins
Patients were contacted by phone and medical records were reviewed at
30 days to ascertain if they have experienced any adverse outcomes
Statistical Primary and dichotomous secondary outcomes were analyzed with chi-
Analysis square tests constructed from binomial regression with a logarithmic link.
The results are expressed as risk ratios with 95% confidence intervals.
Continuous secondary outcomes were assessed with Students t-test or
the Wilcoxon rank-sum test.
Time-to-event outcomes were assessed with Wilcoxon-Breslow-Gehan
test.
Analyses were repeated with adjustment for stratification facts of trial site
and on-pump or off-pump surgery with linear or generalized linear mixed
models, with site as a random effect.
Only unadjusted results are reported.
Results
Baseline Demographic, medical, and perioperative characteristics of the patients
Characteristics were similar throughout both groups.
Table 1 and 2
Results Primary Outcome:
Table 3 Death or thrombotic complication < 30 days
o TXA: 386 patients (16.7%)
o Placebo: 420 patients (18.1%)
o RR 0.92 (95% CI 0.81 to 1.05, P=0.22)
Myocardial Infarction
o TXA: 269 patients (11.6%)
o Placebo: 300 patients (12.9%)
o RR 0.84 (95% CI 0.7 to 1.0, P=0.045)
Rates of death, stroke, pulmonary embolism, renal failure, and bowel
infarction were similar between the two groups.

Bleeding Outcomes:
TXA group had statistically significantly lower rates for the following:
o Number of patients who had blood loss during surgery
o Number of units of blood products that were infused
TXA: 4,331 units; Placebo: 7,994 units
o Number of patients who underwent blood transfusion
o Major hemorrhage or cardiac tamponade leading to
reoperation
TXA: 1.4%; Placebo: 2.8%
NNT with TXA to prevent one reoperation: 71 patients

Postoperative Seizures:
TXA: 15 patients (0.7%); Placebo: 2 patients (0.1%)
o RR 7.6 (95% CI 1.8 to 68.7, P=0.002)
o NNH with TXA to cause one patient to seize: 177 patients
o Patients who had a seizure were more likely to have a stroke
[RR 21.88 (95% CI 10.06 to 47.58, P<0.001)] or to die [RR
9.52 (95% CI 2.53 to 35.9, P=0.02)] < 30 days after surgery
 Authors Conclusion
We found no evidence that the use of tranexamic acid resulted in a higher risk of death or
thrombotic complications than that with placebo.
o However, there was no beneficial reduction in the risk of MI, stroke, or death
despite the blood-sparing effects of tranexamic acid.
Tranexamic acid had a lower risk of blood loss, blood transfusion, and reoperation.
o The lower risk of bleeding with tranexamic acid did not decrease surgery time or
translate to an earlier discharge from the hospital.
Tranexamic acid had a higher risk of postoperative seizures than did the placebo group.
o The relationship of postoperative seizures with stroke and death observed in the
trial suggests a possibly underlying thromboembolic cause of the seizures.
Critique & Discussion
Weaknesses The high dose used in the trial is not comparable to real doses used in our
local practice. While it is helpful to identify the relationship between
tranexamic acid and seizures, it does not translate the risk to normal
dosages in our practice.
The dose-effect relationship was underpowered due to the unexpected
change in trial dose.
There were few patients who were at the highest risk for bleeding or
thrombosis.
Some anesthesiologists were aware of the TXA or placebo assignment.
o Truly blinded data was consistent with outcomes data
There were very few off-pump surgeries.
The wide confidence intervals means the sample size is likely too small, so
conclusions should be replicated with a larger sample size.
Strengths Representative study population
Well matched study groups
Set guidelines for handling excessive bleeding and heparin reversal
Appropriate inclusion and exclusion criteria, defined high-risk patients
Questions to How applicable is this data in our dosing of 10mg/kg or 1000mg?
Ask Why are cardiac surgery patients more vulnerable to tranexamic acid-
associated seizures?
Should tranexamic acid be dose reduced or avoided in patients with a
previous history of a seizure disorder, renal failure, or conditions where the
blood brain barrier is damaged?
Do other antifibrinolytic drugs have a risk of seizures?
Student Authors interpretation of the results are accurate
Conclusions Based upon other studies, the potential mechanism behind the tranexamic
acid-associated seizures is likely related to inhibition of glycine current and
not a thromboembolic cause.
Using a lower dose of tranexamic acid (ex. 1000mg) is likely less of a risk
for proconvulsant effects
Potential prevention or reversal techniques:
o Adjust dose for high-risk patients
o Use general anesthetics, such as propofol and isoflurane, as
first line for prevention and treatment
o For high-risk patients, terminate the tranexamic acid infusion
early and/or prolong the administration of anesthetics during
the postoperative period
Although progress has been made in our understanding of the causes underlying TXAassociated
seizures, many questions remain unanswered. First, it is uncertain why cardiac surgery patients are
more vulnerable to TXAassociated seizures. One potential factor is the high doses of TXA administered
during cardiac surgery.73 Also, cardiac surgery can cause intensive systemic inflammation that increases
the permeability of the bloodbrain barrier.74 A jeopardized bloodbrain barrier could facilitate the
entry of TXA into the CNS. Second, it is important to understand the mechanism by which TXA gains
entry into the CNS, as such knowledge could aid in the development of neuroprotective strategies that
reduce TXA penetration. Third, it is of interest to know whether TXA dosing should be reduced or
avoided in patients with a previous history of a seizure disorder or those with clinical conditions, such as
traumatic brain injury, that damage the bloodbrain barrier and predispose to seizures. Also, antibiotics
such as penicillins and cephalosporins inhibit GABAA receptors and it is unknown whether these drugs
exacerbate the proconvulsant properties of TXA. inally, future studies are needed to determine whether
antifibrinolytic drugs other than TXA also cause seizures.
Based on results from preclinical studies, general anesthetics including propofol and isoflurane may be
considered as the first line for prevention and/or treatment. In highrisk patients, terminating the TXA
infusion early and/or prolonging the administration of anesthetics may prevent seizures.
For example, TXAassociated seizures could be prevented by simply prolonging the delivery of
anesthetics during the early postoperative period. Notably, patients experience seizures most often in
the first few hours after admission to the intensive care unit. At this time, TXA levels are either peaking
or declining slowly.47 In contrast, anesthetic levels are declining rapidly in the CNS, as drug delivery has
been terminated. Potentially Benzos. Dose reduction is simpliest strategy. Dosei s likely factor as txa is a
competitive antagonist of glycine, so a lower dose would be outcompeted.