The Risks of Aprotinin and Tranexamic Acid in Cardiac Surgery: A One-Year Follow-Up
of 1188 Consecutive Patients
Martin, Klaus MD*; Wiesner, Gunther MD*; Breuer, Tamás MD*†; Lange,
Rüdiger MD‡; Tassani, Peter MD*
Author(s):
Section Editor(s): Houge, Charles W. Jr; London, Martin J.; Levy, Jerrold
H.
Issue:
Publication
Type:
Publisher:
Volume 107(6), December 2008, pp 1783-1790
[Cardiovascular Anesthesiology: Cardiovascular and Thoracic Education:
Hemostasis and Transfusion Medicine]
© 2008 by International Anesthesia Research Society.
From the *Institute of Anesthesiology, German Heart Centre Munich,
Munich, Germany; †Department of Cardiology, Semmelweis University,
Budapest, Hungary; and ‡Department of Cardiovascular Surgery,
German Heart Centre Munich, Munich, Germany.
Institution(s): Accepted for publication May 7, 2008.
Address correspondence and reprint requests to Klaus Martin, MD,
Institute of Anesthesiology, German Heart Centre Munich, Clinic at the
Technical University Munich, Lazarettstr. 36. 80636 Munich, Germany.
Address e-mail to martin@dhm.mhn.de.
Abstract
BACKGROUND: Our aim was to investigate postoperative complications and mortality
after administration of aprotinin compared to tranexamic acid in an unselected,
consecutive cohort.
METHODS: Perioperative data from consecutive cardiac surgery patients were
prospectively collected between September 2005 and June 2006 in a universityaffiliated clinic (n = 1188). During the first 5 mo, 596 patients received aprotinin
(Group A); in the next 5 mo, 592 patients were treated with tranexamic acid (Group T).
Except for antifibrinolytic therapy, the anesthetic and surgical protocols remained
unchanged.
RESULTS: The pre- and intraoperative variables were comparable between the
treatment groups. Postoperatively, a significantly higher incidence of seizures was
found in Group T (4.6% vs 1.2%, P < 0.001). This difference was also significant in the
primary valve surgery and the high risk surgery subgroups (7.9% vs 1.2%, P = 0.003; 7.3%
vs 2.4%, P = 0.035, respectively). Persistent atrial fibrillation (7.9% vs 2.3%, P = 0.020)
and renal failure (9.7% vs 1.7%, P = 0.002) were also more common in Group T, in the
primary valve surgery subgroup. On the contrary, among primary coronary artery bypass
surgery patients, there were more acute myocardial infarctions and renal dysfunction
in Group A (5.8% vs 2.0%, P = 0.027; 22.5% vs 15.2%, P = 0.036, respectively). The 1-yr
mortality was significantly higher after aprotinin treatment in the high risk surgery
group (17.7% vs 9.8%, P = 0.034).
CONCLUSION: Both antifibrinolytic drugs bear the risk of adverse outcome depending on
the type of cardiac surgery. Administration of aprotinin should be avoided in coronary
artery bypass graft and high risk patients, whereas administration of tranexamic acid is
not recommended in valve surgery.
In a retrospective analysis of 4374 patients enrolled in the Multicenter Study of
Perioperative Ischemia Research Group international database, aprotinin use was
associated with a higher incidence of adverse outcome, (renal, neurological, and
cardiac) in patients undergoing primary coronary artery bypass surgery (CABG),
compared to patients receiving tranexamic acid, [epsilon]–aminocapronic acid or
control group patients.1 From the same database, a 5-yr follow-up was recently
published.2 The authors concluded that, with regard to the association between
aprotinin, end-organ failure and long-term mortality, the continued use of aprotinin
seems not to be prudent. “Safer alternatives,” such as tranexamic acid or [epsilon]aminocapronic acid, should be used during CABG.
Both studies had an inconsistent demographic bias, especially concerning the patients’
preoperative risk, and had to be mathematically corrected by propensity score
adjustment. The possible influence of unmeasured variables cannot be excluded, and
the question remains whether the increased prevalence of adverse outcomes is a
consequence of different perioperative risk factors.
For many years at our institution aprotinin has been used in almost every patient
undergoing cardiac surgery with extracorporeal circulation.3 As a consequence of the
serious concerns about the safety of aprotinin, we decided to completely stop using
aprotinin in February 2006, and to use tranexamic acid instead, as the antifibrinolytic
drug of choice during cardiac surgery.
This consequent treatment with one of the antifibrinolytic drugs offered us the
opportunity to create two treatment groups of our consecutive patients without any
preselection. In this study, we compared data of a 5-mo period of administering
tranexamic acid with data of the preceding 5 mo of aprotinin administration in almost
1200 consecutive adult cardiac surgery patients undergoing extracorporeal circulation
with regard to blood loss, cardiac, renal, and neurological complications, as well as 30day, and 1-yr mortality.
Although not randomized, this study meets most criteria of a randomized clinical trial
without the need to use statistical methods for risk adjustment, in contrast to the
other recently published studies on this topic.
METHODS
The study was approved by the Ethical Committee of the Technical University Munich
(Germany); the requirement for written informed consent was waived by the board.
After approval, we analyzed the perioperative data of all adult patients undergoing
cardiac surgery using cardiopulmonary bypass (CPB) between September 2005 and June
2006 (n = 1239). Patients were excluded if they did not receive any antifibrinolytic
therapy, received multiple drugs, or the administered dose of the antifibrinolytic drug
was not sufficient according to our institutional protocol (total dose <4 × 106 kallikrein
inhibiting units (KIU) aprotinin or 4 g tranexamic acid, respectively). If a patient
underwent reoperation for nonbleeding reasons during the same admission, only data of
the first operation were included in the analyses. After exclusion, the study cohort
contained data of 1188 consecutive patients (Fig. 1). Data of the patients were
prospectively collected in the clinical database as part of the national quality
assurance project in cardiac anesthesia and surgery. Laboratory values were extracted
from the database of the clinical laboratory.
Figure 1. Diagram of patient enrollment. CPB, cardiopulmonary bypass.
Until February 2006, all patients undergoing cardiac surgery with CPB were treated
with full-dose aprotinin (Trasylol; Bayer, Leverkusen, Germany) according to the
Hammersmith protocol (Group A). The Hammersmith protocol consists of a bolus of 2 ×
106 KIU aprotinin administered at the beginning of CPB, followed by a continuous
infusion of 0.5 × 106 KIU/h until chest closure; 2 × 106 KIU is added to the prime of the
CPB equipment. From February 2006 onward, aprotinin was completely replaced by
tranexamic acid (Cyklokapron; Pfizer, Karlsruhe, Deutschland) (Group T). Tranexamic
acid was administered according to the institutional protocol: 2 g was administered at
the beginning of CPB and then as a continuous infusion at a rate of 0.5 g/h until chest
closure; 2 g was added to the prime of the CPB equipment. We compared perioperative
data of the patients from the first 5-mo period of using tranexamic acid (Group T, n =
592) with data of patients from the preceding 5 mo of aprotinin administration (Group
A, n = 596). All other aspects of the surgical and anesthetic management remained
unchanged.
A standard CPB setting was used. After cross-clamping of the aorta, either 1500 mL of
cold crystalloid cardioplegic solution (Bretschneider = Custodiol; Köhler Chemie,
Alsbach-Hahnlein, Germany) for any surgery involving valves or warm bloodcardioplegia (CABG surgery only) was used for cardiac arrest. Transfusion triggers used
were a hematocrit decrease to <18% on CPB or <24% during the postoperative course, or
if the patient showed clinical signs indicating the need for a higher oxygen supply.
Inotropic support was defined as the continuous infusion of at least two of the
following: more than 5 µg · kg · min-1 dopamine or dobutamine, or epinephrine or
milrinone, respectively. Vasopressor therapy was defined as the application of
norepinephrine of at least 500 µg/h.
We analyzed the main demographic data, the medical history data, the intraoperative
data, and the type of surgery. Postoperative blood loss was measured as chest-tube
output at 6, 12, and 24 h after surgery. The amount of transfused allogenic blood
products and reoperation for bleeding were also recorded. Postoperative renal
dysfunction required a serum creatinine level of >1.3 mg/dL with an increase over
baseline of at least 0.5 mg/dL; renal failure was defined as dysfunction requiring
dialysis. Cardiac complications were new persistent atrial fibrillation (new atrial
fibrillation continuing until discharge from the intensive care unit), acute myocardial
infarction (AMI; new Q-waves, persistent ST-segment or T-wave changes and CK-MB
higher than three times the upper limit of normal range of our institution protocol,
i.e., >80 U/L),29 and heart failure (need for inotropic support and intraaortic ballon
pump). Neurological events, defined as new seizure or stroke/transitory ischemic
attack, were clinically diagnosed; stroke was confirmed by computed tomography scan.
Mortality (all-cause death) was assessed 30 days and 1-yr after surgery. Foreign
patients were primarily excluded from follow-up (primary loss). A questionnaire was
sent to all patients who were not taking part in routine examination at 1-yr after
surgery. If necessary, the patients’ cardiologists or the local authorities were
contacted. Nonresponders were also excluded (secondary loss).
We analyzed data of the whole cohort together (ALL). For post hoc analysis, this
collective was split in three subgroups according to the type of surgery: primary CABG,
primary valve surgery (VALVE); i.e., left heart valve surgery (mitral and/or aortic
valve), and high risk surgery (HIGH RISK) operations for bleeding, e.g., combined and
redo operations, aortic surgery, etc. (Table 1).
Table 1. Different Types of Operations in the Study Cohort
Continuous data are presented as mean ± sd (SD), categorical variables as number (N),
and incidence (%). Parameters were compared between Group A and Group T using
Mann-Whitney U-test for continuous variables and [chi]2 test for categorical variables.
For [chi]2 analysis, the effective total sample size to achieve a power level of 0.8
([alpha] = 0.05, estimated effect size = 0.2, df = 1) was 197 (GPOWER for MS-DOS,
Franz Faul & Edgar Erdfelder, Bonn, Germany). The difference in mortality between
the treatment groups was assessed by Kaplan-Meier analysis and Mantel–Cox log-rank
test. The results of the two-sided tests were considered significant if the P value was
<0.05. The statistical analyses were performed by SPSS for Windows 14.0 statistical
software package (SPSS Inc., Chicago, IL).
RESULTS
There was similar distribution of type of surgery in the treatment groups (Table 1). The
main pre- and intraoperative data are presented in Table 2. The only difference in the
entire cohort was that more patients were medicated with clopidogrel in Group A. In
the subgroups, we found some minor differences (Table 2.). The 10 most experienced
surgeons and anesthesiologists performed 92% and 83% of the operations in Group T,
and 93% and 85% in Group A, respectively.
Table 2. Preoperative and Operative Data of the Patients
In ALL patients, the postoperative blood loss and the postoperative transfusion of red
blood cells and fresh frozen plasma were significantly decreased in Group A (Table 3.).
Subgroup analyses showed significantly less blood loss after administration of aprotinin
at all time points in all subgroups, whereas the amount of transfused blood products
was significantly smaller only in the VALVE subgroup postoperatively (Table 3).
Table 3. Blood Loss and Transfusion of Blood Products
Outcome data of the patients are presented in Table 4. Analyzing ALL patients, the
incidences of persistent atrial fibrillation and seizure were significantly higher in Group
T; the incidence of AMI was higher in Group A. Subgroup analyses showed that in the
primary CABG group there were more AMI and renal dysfunction after aprotinin
treatment. Administration of tranexamic acid was associated with a higher incidence of
seizure, atrial fibrillation, and renal failure in the VALVE subgroup, and with a higher
incidence of seizure in the HIGH RISK patients.
Table 4. Outcome Data of the Patients
Follow-up for mortality was conducted in 96.5% of the patients. Mortality in ALL
patients showed no significant difference between the treatment groups. We have not
found any significant difference in 30-day mortality in the subgroups, but 1-yr mortality
was significantly higher in the HIGH RISK group after aprotinin treatment (Table 5, Fig.
2).
Table 5. Mortality of the Patients
Figure 2. Kaplan–Meier analysis of 30-day (A) and 1-yr mortality (B) in the HIGH RISK
group. Group tranexamic acid contains 177 patients, group aprotinin contains 166
patients.
DISCUSSION
As every consecutive patient was included in our analysis, we generated an unselected
population with only minor differences in the preoperative and intraoperative data. We
assumed that the unmeasured variables were also comparable and therefore, no
mathematical adjustment, such as propensity score method, was necessary for further
analysis. This is an important difference to recently published retrospective
studies.1,2,5–7
The efficacy of antifibrinolytic drugs on blood loss and perioperative transfusion of
donor blood has been described.8 The blood-sparing effect of aprotinin was often
superior to that of tranexamic acid 9,10 and aminocapronic acid, but not
always.6,11,12 Our data showed that patients receiving aprotinin during cardiac
surgery had significantly lower postoperative blood loss compared to patients receiving
tranexamic acid. This benefit was detected in the entire cohort and all subgroups, but
it had no effect on the amount of transfusion in the CABG and HIGH RISK patients.
Thus, it is still questionable whether the statistically smaller blood loss in Group A is
really clinically relevant.
Besides the well documented reduction of blood loss, antifibrinolytic drugs might have
some unexpected effects, which were often not assessed in the studies focusing on
postoperative blood loss and transfusion rates only. Some investigators have
demonstrated that aprotinin decreases mortality in cardiac surgery 13 and reduces the
incidences of stroke or encephalopathy.14,15 Others have demonstrated an increased
risk of myocardial infarction, stroke or encephalopathy, renal failure,1 renal failure
only,5 and even mortality.2 The latter publications have received an enormous public
reaction and even the Food Drug Administration has questioned the use of aprotinin.*
These studies are still under discussion due to the statistically significant differences in
baseline characteristics which had to be corrected by propensity score adjustment. This
always leaves unanswered questions about an unmeasured selection which might have
led to the higher incidences of adverse outcomes.16
As previously described, aprotinin has a high affinity to the kidneys and may lead to
disturbances in kinin-synthesis and release, renal afferent vasoconstriction, and macroand microvascular thrombosis.17,18 The phenomenon of arterial vasoconstriction with
a probable intravascular thrombosis has also been observed in an animal model in the
coronary 19 and femoral arteries.20 However, the underlying mechanism is still
unclear.
In our study, there was neither a difference in postoperative renal dysfunction nor in
the requirement for dialysis between the two treatment groups of the entire
population. We set the criteria for postoperative renal dysfunction at a low serum
creatinine level, (>1.3 mg/dL = 115 µmol/L) accompanied by an increase from baseline
(>=0.5 mg/dL = 44 µmol/L) to detect even milder forms of dysfunction. The overall
incidence of dialysis between 5%–6% is well within the range of the literature,1,5
especially in view of the inclusion of high risk patients in our cohort. Contrary to the
results of Group ALL, we found a significantly higher rate of renal dysfunction with
aprotinin in the CABG subgroup. Although not reaching significance, the percentage of
renal failure was twofold compared to Group T. Our data support previous findings of
an increased risk of renal complications in patients receiving aprotinin during primary
CABG surgery.1,5
The CABG and HIGH RISK subgroups were defined by similar criteria as in other studies,
which described higher incidences of myocardial infarction 1 and death after
aprotinin.2† Two recently published retrospective analyses of large CABG cohorts also
reported, an increased risk for in-hospital death 6 and reduced long-term survival 7
among aprotinin recipients. We recorded a higher rate of myocardial infarctions in the
CABG patients as well. Additionally, there was a tendency for more short-term
mortalities in both CABG and HIGH RISK subgroups. The lack of significance might be
related to the limited number of patients and fatal events. Nevertheless, 1-yr mortality
was significantly increased after aprotinin treatment in the HIGH RISK patients. The
finding of an increased mortality with aprotinin in patients at high risk for bleeding is in
agreement with the results of the interim analyses of the BART study, which led to the
suspension of marketing aprotinin.‡
Another major finding of our study is the much higher rate of seizures after
administration of tranexamic acid. Tranexamic acid has been shown to have an
epileptogenic effect if it is applied topically to the cortex,21,22 intrathecally 23 or
even IV in animals.22 The suspected mechanism is a [gamma]-aminobutyric acid-driven
inhibition of the central nervous system.24 Some neurosurgical studies have shown a
higher incidence of cerebral vasospasm after topical use of tranexamic acid in patients
suffering from subarachnoid hemorrhage,25 and also in an animal model.26 Our finding
might be related to tranexamic acid-induced vasoconstriction and to concomitant
microcirculatory disturbances.
The pathomechanism of seizures detected in our study is not yet determined. They
occurred almost exclusively after open heart surgery, in VALVE and HIGH RISK patients
receiving tranexamic acid. Therefore, it seems reasonable that this complication was
associated with the different management of these patients. One possible explanation
is the electrolyte change due to the administration of crystalloid cardioplegia during
valve surgery; another is the possible effect of microbubbles, which inevitably remain
after closing the heart. Additionally, in the VALVE subgroup, the tranexamic acid
patients had renal failure and persistent atrial fibrillation more frequently. These
complications might have resulted in the tendency towards more short-term mortalities
in this subgroup after tranexamic acid treatment. Since there are no large studies
focusing on the safety of tranexamic acid, especially in valve surgery, this should be a
topic of future research.
LIMITATIONS
Our study compared data of two chronologically close patient cohorts. Therefore, the
risk of unrecognized changes in practice is reduced to a minimum, but it cannot be
excluded completely. However, due to the study design and the fact that the known
variables were comparable, we assumed that the groups matched well and the
unknown variables were also comparable.
There were a considerable number of consecutive patients in total and the sample size
exceeded the calculated sample size for a power of 0.8 in all the subgroups. However,
we cannot exclude that the study did not have enough power to detect all the
differences between the treatment groups. Comparative trials powered for important
clinical end-points are needed before any antifibrinolytic drug is routinely prescribed
for a large number of patients.27
Although we made multiple comparisons in our analyses, we did not adjust the P value
because doing so would have increased the chance of making Type II errors.28 Since our
focus was on the possible side effects of antifibrinolytics, this appeared not to be
prudent. Nevertheless, even with correction for multiple comparisons, the increased
rate of seizures with tranexamic acid in valve surgery is a main finding of our study.
CONCLUSIONS
The blood-sparing effect of aprotinin after cardiac surgery was superior to that of
tranexamic acid, but the clinical relevance of this remains questionable. The benefit of
the blood-sparing effect has to be balanced against the potential risks of
antifibrinolytic drugs.
Aprotinin was associated with a higher incidence of complications after primary CABG
surgery and a higher 1-yr mortality in HIGH RISK patients compared to tranexamic acid.
In addition, this is the first study reporting the detrimental effects of tranexamic acid
after valve surgery.
Our results show that both antifibrinolytic drugs bear risks of adverse effects that might
worsen outcome. Administration of aprotinin should be avoided in CABG and HIGH RISK
patients. Tranexamic acid should not be used in open heart procedures until the
mechanism of the side effects is clear.
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