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01.08.2010 | Research | Ausgabe 4/2010 Open Access

Critical Care 4/2010

Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis

Zeitschrift:
Critical Care > Ausgabe 4/2010
Autoren:
Michael Sander, Claudia D Spies, Viktoria Martiny, Christoph Rosenthal, Klaus-Dieter Wernecke, Christian von Heymann
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​cc9216) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests. This work was supported by institutional grants from Charité-Universitätsmedizin, Berlin, Germany.

Authors' contributions

MS and CvH prepared the manuscript, conceived the study, and performed the statistical analysis. MS, CvH, and VM carried out the data acquisition; KDW prepared the statistical part of the manuscript and performed the statistical analysis. CR and CS drafted the manuscript and helped with the study design and coordination. All authors read and approved the final manuscript.
Abbreviations
APACHE II
acute physiology and chronic health evaluation score II
AT III
antithrombin
CABG
coronary artery bypass graft
CI
confidence interval
CK
creatinine kinase
CK-MB
creatinine kinase isoenzyme MB
COPD
chronic obstructive pulmonary disease
CPB
cardiopulmonary bypass
CVP
central venous pressure
EF
ejection fraction
FFP
fresh frozen plasma
FiO2
inspiratory oxygen fraction
GABA
γ-aminobutyric acid
Hct
hematocrit
ICU
intensive care unit
IMCU
intermediate care unit
MAP
mean arterial pressure
OR
odds ratio
PC
platelet concentrate
pO2
partial pressure of oxygen
POD
postoperative day
PPSB
coagulation factor concentrate (prothrombin, factor VII, factor X, factor IX)
PRBCs
packed red blood cells
ROC
receiver operating characteristic
SAPS
simplified acute physiological score
SD
standard deviation
SIRS
systemic inflammatory response syndrome
TXA
tranexamic acid
WBC
white blood cell count.

Introduction

Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. In 2006, the use of aprotinin became controversial when the drug was associated with an increased risk of renal failure, myocardial infarction, stroke, and death in a large observational study [1]. Retrospective analyzed data from the Mc SPI database published by Mangano et al. [1, 2] seemed to show that the use of aprotinin was associated with the increased risk of postoperative complications after cardiac surgery and even with an increased mortality. The authors of this study concluded that the association between aprotinin and serious end-organ damage indicates that its continued use is not prudent [1]. In contrast, the less-expensive generic medications ε-aminocaproic acid and tranexamic acid (TXA) would be safe alternatives. However, this conclusion might be problematic, being drawn for all types of cardiac surgical patients from a retrospective study. However, subsequent published cohort studies also linked aprotinin to an increased risk of morbidity and mortality [25].
In 2007, data from the BART trial were published [6]. The BART trial originally was designed as a multicenter trial looking into whether aprotinin was superior to TXA and aminocaproic acid in decreasing the risk of massive postoperative bleeding in patients undergoing high-risk cardiac surgery. The trial was terminated early because of a higher rate of death in patients receiving aprotinin [6]. Since aprotinin has been withdrawn from the market in many countries, TXA has become the routine antifibrinolytic therapy of choice. Recently, however, evidence indicated that the application of TXA might be associated with morbidity as well. Noteworthy are especially neurologic complications that have been shown by recent studies, especially in pediatric patients and in patients undergoing open-heart procedures [79]. From this point of view, it is crucial to know the safety profile of different antifibrinolytic therapies in cardiac surgery to prevent any harm in patients at risk. This is especially important in the context of the work of Karkouti [10], showing that from their single-center experience, high-risk patients given TXA had an excessive complication rate.
Therefore, the aim of this prospective observatory study was to evaluate the safety and efficiency profile of TXA compared with aprotinin in patients undergoing cardiac surgery with CPB and in patients with open-heart procedures, as was suggested recently [7].

Materials and methods

Group assignment

After publication of the first Mangano article raising concerns about the safety profile of aprotinin, we changed our routine administration of antifibrinolytics. On July 1, 2006, we discontinued the use of aprotinin. From that time, we prospectively collected anonymized data in a database evaluating parameters of efficiency and safety. Data of 336 patients receiving TXA were compared with retrospectively collected data from 557 consecutive patients receiving aprotinin undergoing cardiac surgery with cardiopulmonary bypass (CPB) during the 6 months before the change in our antifibrinolytic practice. Patients gave consent for observational studies in our institution. The local ethics committee approved this observational study. A subgroup of 320 patients undergoing open-heart procedures (105 receiving TXA and 215 receiving aprotinin) was analyzed separately (Figure 1).

Anesthetic, cardiopulmonary bypass, and intensive care management

Our standard anesthetic practice for patients undergoing cardiac surgery with CPB is to use etomidate, sufentanil, and pancuronium for induction and sevoflurane, with propofol and sufentanil infusion for maintenance. In all patients, a radial artery was punctured before induction. The radial artery catheter was used for measurement of arterial blood pressure and to obtain blood samples for point-of-care blood gas analysis (ABL-700 series; Radiometer, Copenhagen, Denmark). A central venous catheter was inserted via the right internal jugular vein.
The prime for the cardiopulmonary bypass circuit consisted of 600 ml of crystalloid fluid, 500 ml of 6% hydroxyethylstarch (HES) solution (Voluven; Fresenius-Kabi, Bad Homburg, Germany). A total dose of 50,000 KIU aprotinin per kilogram bodyweight was administered during CPB in the aprotinin group. The TXA group received 50 mg/kg bodyweight as a bolus before CPB and 50 mg/kg bodyweight into the CPB circuit. Pump flow was adjusted to maintain a mean arterial pressure (MAP) of 55 to 60 mm Hg and a venous oxygen saturation >75% during CPB. When the MAP could not be maintained by adjusting the pump flow, norepinephrine was used. During cardiopulmonary bypass, a partial arterial pressure of oxygen (paO2) of 150 to 250 mm Hg was maintained. Body temperature was kept between 35.5 and 36.0°C during CPB, and intermittent antegrade warm-blood cardioplegia was used as described by Calafiore [11]. After surgery, all patients were transferred to the ICU. ICU management and transfusion practice did not differ between patients of both groups. After ICU treatment, all patients were first transferred to the intermediate care unit (IMCU).

Database management

The prospective data collection begun on July 1, 2006, when the first patient received routinely TXA for cardiac surgery, according to our revised standard operating procedures. Into the same database, we retrospectively collected consecutive data from the last 6 months from patients receiving aprotinin for cardiac surgery with CPB (beginning from January 2 until June 30, 2006).
Safety was evaluated by routinely monitored myocardial biomarkers (creatinine kinase (CK) and isoenzyme MB (CK-MB), creatinine, and the diagnosis of myocardial infarction, ischemic stroke, intracerebral hemorrhage, convulsive seizures, and acute renal failure during ICU and IMCU stay. Efficiency was documented in this database by the need for transfusion of blood products (erythrocyte concentrates, fresh frozen plasma, and platelet concentrates) and total postoperative blood loss (first 6 h after surgery, 24 h after surgery, until 48 hours after surgery), as well as the number of surgical reexplorations for bleeding. We documented in-hospital mortality, duration of ventilation, ICU treatment, and hospital stay as further outcome parameters. All complications were graded as early (during ICU stay) and late (during further hospital stay). Transfusion was guided by our written and published local standard operating procedures.
The diagnosis of myocardial infarction was based on the presence of new Q waves in two contiguous electrocardiogram leads and an increase of myocardial creatine kinase (CK-MB) above 10% of total creatine kinase (CK) or confirmed graft occlusion within the first 30 days after surgery. Ischemic stroke was defined as a focal neurologic deficit lasting more than 24 h and had to be confirmed by a cerebral CT scan and the attending neurologic consultant. Neurologic disability was defined as any newly developed neurologic impairment that lasted longer than 24 h and had to be confirmed by a neurologic consultant. Convulsive seizures were defined as clinically apparent seizures. All patients with seizures underwent routine cerebral CT scan to exclude ischemia or bleeding. Acute renal failure was defined as a decrease in urine output below 500 ml/24 h, the need for at least one dialysis treatment, a doubling of the baseline serum creatinine level, or a postoperative serum creatinine level of more than 150 μmol/L (1.7 mg/dl) with normal creatinine before surgery. Thrombembolic cause of death was defined as death due to a thromboembolic event (for example, myocardial infarction, ischemic stroke, pulmonary embolism).
The group of patients undergoing open-heart procedures was defined as valve surgery, CABG with atrial ablation procedures on the ascending aorta, ventriculotomy, and atrial and ventricular septal defect repair.

Statistical methods

Results were expressed as mean ± standard deviation (SD) in case of continuous variables. Absolute and relative frequencies were used for categoric and dichotomous variables. The effect on outcome variables was analyzed by using the Exact χ2 test for categoric and dichotomous variables. A check for normal distribution did not reveal substantial deviations from normality (Lilliefors test); therefore, we applied the t test for comparisons of independent groups in case of continuous variables.
Multivariate backward stepwise logistic regression analysis with mortality as the response was accomplished to investigate the impact of interesting clinical characteristics such as age, CPB time, Euro II Score, type of surgery, creatinine, hemoglobin, and type of antifibrinolytic. Odds ratios (ORs) with 95% confidence intervals (CIs) and the corresponding P values were determined. Changes in blood loss over time were analyzed by using nonparametric analysis of longitudinal data in a two-factorial design (first factor: TXA vs. aprotinin; second factor: Time). Therefore, we compared all the time points simultaneously on the corresponding response curves. The P values for differences between groups (first factor) were marked with Pgroups, for changes in time (second factor) with Ptime, and for interactions (differences increase with time) with Pintact.
As this study was designed as an exploratory investigation, no statistical sample size (power) calculation was conducted.
A P value < 0.05 (two-sided) was considered statistically significant. Multiple testing for differences between the groups in question was regarded as exploratory and not confirmatory; therefore, no adjustments for multiplicity were made. Confirmatory studies should use data from this study for the design of an adequately powered trial confirming our results.
Statistical analysis was carried out by using the Software Package for Social Sciences, 16.0 SPSS® for Macintosh (SPSS, Inc., Chicago, IL).

Results

During the 12-month study period, we included 893 patients undergoing cardiac surgery with CPB into our database, with a group of 557 consecutive patients receiving aprotinin and 336 patients receiving TXA (Figure 1).
Patient's baseline characteristics are shown in Table 1. No significant differences were found with regard to baseline characteristics, with the exception of preoperative hemoglobin being significantly lower in patients in the TXA group (13.1 mg/dL ± 2.0 versus 13.6 mg/dL ± 1.8; P < 0.01). In Table 2, types of surgery are displayed. Surgery-type related data (Table 2) did not differ between groups (P = 0.15). Also the EUROSCORE II did not differ (6.3 ± 3.9 aprotinin group versus 5.8 ± 3.7 TXA group; P = 0.08). Furthermore, no significant differences were noted between both groups with regard to comorbidities as diabetes mellitus (P = 0.71), peripheral vascular disease (P = 0.76), renal insufficiency (P = 0.10), and COPD (P = 0.47). No significant difference existed between both groups concerning the treatment with and, if treated, how many days before surgery the vitamin K antagonist, clopidogrel, and acetylsalicylic acid were paused.
Table 1
Baseline characteristics of the patients in the aprotinin and tranexamic acid groups
 
Aprotinin
Tranexamic acid
 
 
Mean
SD
Mean
SD
P
Age (years)
     
All patients
68
11
67
11
0.09
Open-heart procedures
69
11
68
13
0.25
Height (cm)
     
All patients
171
9
172
9
0.88
Open-heart procedures
171
9
170
11
0.71
Weight (kg)
     
All patients
80
15
80
16
0.74
Open-heart procedures
77
17
77
15
0.94
Ejection fraction preop (%)
     
All patients
55
15
53
15
0.20
Open-heart procedures
53
14
51
16
0.18
Creatinine preop (mg/dL)
     
All patients
1.18
0.76
1.24
0.87
0.28
Open-heart procedures
1.14
0.46
1.31
1.03
0.04
Platelets preop (/nL)
     
All patients
235
88
239
80
0.51
Open-heart procedures
241
86
241
88
0.97
WBC preop (/nL)
     
All patients
8.3
4.2
8.1
2.9
0.37
Open-heart procedures
8.4
4.2
8.1
3.5
0.55
Hemoglobin preop (mg/dL)
     
All patients
13.6
1.8
13.1
2.0
< 0.01
Open-heart procedures
13.2
1.9
12.5
1.8
< 0.01
Prothrombin time preop (%)
     
All patients
93
15
93
14
0.69
Open-heart procedures
91
17
88
16
0.15
PTT preop (s)
     
All patients
41.1
23.7
42.3
24.0
0.49
Open-heart procedures
40.6
22.2
41.3
17.8
0.76
AT III preop (%)
     
All patients
97
15
95
17
0.17
Open-heart procedures
97
14
93
19
0.05
AT III, antithrombin; PTT, partial thromboplastin time; SD, standard deviation; WBC, white blood cell count.
Table 2
Surgical, ICU, and outcome data of patients receiving aprotinin and tranexamic acid
  
Aprotinin
Tranexamic acid
 
CABG
n
349
231
 
 
% in group
63.1%
69.0%
 
Valve
n
106
48
 
 
% in group
19.2%
14.3%
 
Double valve
n
11
2
 
 
% in group
2.0%
0.6%
 
CABG plus valve
n
68
41
 
 
% in group
12.3%
12.2%
 
Other
n
19
13
 
 
% in group
3.4%
3.9%
 
  
Mean
SD
Mean
SD
P
Duration of surgery (min)
     
All patients
206
60
211
71
0.28
Open-heart procedures
210
65
235
79
< 0.01
CPB time (min)
     
All patients
89
42
88
46
0.79
Open-heart procedures
104
47
114
53
0.07
Cross-clamp time (min)
     
All patients
59
34
57
36
0.37
Open-heart procedures
77
40
85
43
0.08
Euroscore II
     
All patients
6.3
3.9
5.8
3.7
0.08
Open-heart procedures
7.7
3.6
7.3
3.7
0.42
ICU treatment (days)
     
All patients
3.1
9.5
3.5
8.1
0.51
Open-heart procedures
4.3
13.8
5.7
11.8
0.38
Hospital stay (days)
     
All patients
17.0
17.1
18.9
18.6
0.11
Open-heart procedures
20.8
20.8
23.6
25.1
0.28
Mechanical ventilation (h)
     
All patients
25.6
128.0
45.4
187.3
0.06
Open-heart procedures
36.3
188.4
83.0
263.6
0.07
APACHE II (admission ICU)
     
All patients
19.4
6.8
19.3
7.0
0.89
Open-heart procedures
20.2
7.3
19.8
6.7
0.60
SAPS II (admission ICU)
     
All patients
34.3
12.4
36.4
12.5
0.02
Open-heart procedures
36.7
13.0
39.7
13.1
0.06
APACHE II, acute physiology and chronic health evaluation score II; CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass; ICU, intensive care unit; SAPS, simplified acute physiological score; SD, standard deviation.
Analysis of biochemical safety data revealed no differences between both groups, with the exception of a slight increase of creatinine in patients receiving TXA immediately after surgery (1.2 mg/dL ± 0.8 versus 1.1 mg/dL ± 0.7; P = 0.02). The PT ratio and PTT were slightly different between both groups (Table 3). Acute renal failure was identical between groups (9.4% aprotinin versus 11.6% TXA, P = 0.31). However, acute renal failure was seen more often in patients receiving TXA (13.7%) compared with patients receiving aprotinin (8.5%; P = 0.02).
Table 3
Biochemical data of patients receiving aprotinin and tranexamic acid
 
Aprotinin
Tranexamic acid
 
 
Mean
SD
Mean
SD
P
Creatinine after surgery (mg/dL)
     
All patients
1.1
0.7
1.2
0.8
0.02
Open-heart procedures
1.08
0.50
1.30
0.73
< 0.01
Creatinine POD 1 (mg/dL)
     
All patients
1.5
5.3
2.2
14.0
0.29
Open-heart procedures
1.37
1.83
1.42
0.65
0.77
CK after surgery (U/mL)
     
All patients
521
635
474
782
0.33
Open-heart procedures
521
605
589
1307
0.53
CK-MB after surgery (U/mL)
     
All patients
59
64
54
69
0.27
Open-heart procedures
59
64
77
109
0.39
CK POD 1 (U/mL)
     
All patients
1013
1496
878
1131
0.16
Open-heart procedures
1032
1462
914
1224
0.48
CK-MB POD 1 (U/mL)
     
All patients
55
69
52
80
0.51
Open-heart procedures
59
64
67
103
0.42
WBC after surgery (/nL)
     
All patients
12.6
5.5
12.5
5.4
0.80
Open-heart procedures
13.6
5.7
13.8
6.3
0.74
WBC POD 1 (/nL)
     
All patients
14.0
4.4
13.8
6.9
0.63
Open-heart procedures
14.4
4.4
13.4
4.2
0.04
Hemoglobin after surgery (g/dL)
     
All patients
10.2
1.2
10.5
7.3
0.27
Open-heart procedures
10.1
1.4
11.1
12.9
0.26
Hemoglobin POD 1 (g/dL)
     
All patients
10.4
1.2
10.3
3.8
0.77
Open-heart procedures
10.3
1.1
10.7
6.6
0.44
Platelets after surgery (/nL)
     
All patients
144
50
153
56
0.01
Open-heart procedures
143
55
149
62
0.35
Platelets POD 1 (/nL)
     
All patients
158
55
160
57
0.53
Open-heart procedures
147
59
145
59
0.75
PT ratio after surgery (%)
     
All patients
65
10
64
10
0.03
Open-heart procedures
64
11
61
10
< 0.01
PT ratio POD 1 (%)
     
All patients
75
12
74
11
0.04
Open-heart procedures
73
13
71
13
0.12
aPTT after surgery (s)
     
All patients
51.0
16.7
41.0
14.5
< 0.01
Open-heart procedures
53.6
19.0
43.4
21.0
< 0.01
aPTT POD 1 (s)
     
All patients
44.0
15.1
41.2
10.3
< 0.01
Open-heart procedures
46.6
17.9
42.7
12.2
0.05
AT III after surgery (%)
     
All patients
67
12
68
13
0.37
Open-heart procedures
69
12
69
15
0.67
AT III POD 1 (%)
     
All patients
76
14
74
14
0.31
Open-heart procedures
78
13
75
15
0.34
AT III, antithrombin; CK, creatinine kinase; CK-MB, creatinine kinase isoenzyme MB; POD, postoperative day; PT, prothrombin ratio; PTT, partial thromboplastin time; SD, standard deviation; WBC, white blood cell count.
Patients receiving aprotinin had a higher rate of late events of ischemic stroke (3.4% versus 0.9%; P = 0.02) and late neurologic disability (5.8% versus 2.4%; P = 0.02). The rate of postoperative convulsive seizures in the ICU was increased in tendency in patients receiving TXA (2.7% versus 0.9%; P = 0.05) compared with patients receiving aprotinin. No difference regarding myocardial infarction, intracerebral hemorrhage, and acute renal failure was observed (Table 4). In-hospital mortality in all patients did not differ between both groups (6.9% aprotinin versus 8.7% TXA; P = 0.34).
Table 4
Safety data of patients receiving aprotinin and tranexamic acid
   
Aprotinin
Tranexamic acid
P
Myocardial infarction (ICU)
All patients
N
8
6
0.78
 
Open-heart procedures
 
0
2
0.04
 
All patients
% in group
1.4%
1.8%
 
 
Open-heart procedures
 
0.0%
1.9%
 
Myocardial infarction (late)
All patients
N
7
5
0.77
 
Open-heart procedures
 
1
1
0.60
 
All patients
% in group
1.3%
1.5%
 
 
Open-heart procedures
 
0.5%
1.0%
 
Seizures (ICU)
All patients
N
5
9
0.05
 
Open-heart procedures
 
4
7
0.04
 
All patients
% in group
0.9%
2.7%
 
 
Open-heart procedures
 
1.9%
6.7%
 
Seizures (late)
All patients
N
6
1
0.20
 
Open-heart procedures
 
3
1
0.74
 
All patients
% in group
1.1%
0.3%
 
 
Open-heart procedures
 
1.4%
1.0%
 
Ischemic stroke (ICU)
All patients
N
21
9
0.45
 
Open-heart procedures
 
10
6
0.68
 
All patients
% in group
3.8%
2.7%
 
 
Open-heart procedures
 
4.7%
5.7%
 
Ischemic stroke (late)
All patients
N
19
3
0.02
 
Open-heart procedures
 
9
1
0.12
 
All patients
% in group
3.4%
0.9%
 
 
Open-heart procedures
 
4.2%
1.0%
 
Neurologic disability (ICU)
All patients
N
21
11
0.85
 
Open-heart procedures
 
12
9
0.34
 
All patients
% in group
3.8%
3.3%
 
 
Open-heart procedures
 
5.6%
8.6%
 
Neurologic disability (late)
All patients
N
32
8
0.02
 
Open-heart procedures
 
15
1
0.03
 
All patients
% in group
5.8%
2.4%
 
 
Open-heart procedures
 
7.0%
1.0%
 
Intracerebral hemorrhage (ICU)
All patients
N
3
1
1.00
 
Open-heart procedures
 
2
1
1.00
 
All patients
% in group
0.5%
0.3%
 
 
Open-heart procedures
 
0.9%
1.0%
 
Intracerebral hemorrhage (late)
All patients
N
1
0
1.00
 
Open-heart procedures
 
0
0
n/a
 
All patients
% in group
0.2%
0.0%
 
 
Open-heart procedures
 
0.0%
0.0%
 
Mortality (in-hospital)
All patients
N
38
29
0.34
 
Open-heart procedures
 
16
17
0.02
 
All patients
% in group
6.9%
8.7%
 
 
Open-heart procedures
 
7.5%
16.2%
 
Patients in the TXA group showed a trend for prolonged need of mechanical ventilation (45.4 h ± 187.3 versus 25.6 h ± 128.0; P = 0.06. This led in tendency to a prolonged hospital stay of 2 days compared with the aprotinin group (18.9 days ± 18.6 versus 17.0 days ± 17.1; P = 0.11) (Table 2).
Patients being treated with TXA had increased cumulative drainage losses at 6, 24, and 48 h after surgery (Figure 2a; Table 5) compared with patients receiving aprotinin (Pgroups < 0.01; Ptime < 0.01; Pintact < 0.01). These patients did receive significantly more packed red cells, units of fresh frozen plasma, and platelet concentrates (Table 5) compared with patients receiving aprotinin. The use of aprotinin was associated with a decreased risk of being transfused with packed red cells (P < 0.01), units of fresh frozen plasma (P < 0.01), and platelet concentrates (P < 0.01) (Figure 3a). Furthermore, the use of TXA was associated with an increased rate of repeated thoracotomy for bleeding (6.9% versus 2.4%; P < 0.01).
Table 5
Blood loss, transfusion, and coagulation-related data for patients receiving aprotinin and tranexamic acid
  
Aprotinin
Tranexamic acid
 
  
Mean
SD
Mean
SD
P
Blood loss first 6 h (mL)
     
All patients
230
338
366
492
< 0.01
Open-heart procedures
229
260
459
616
< 0.01
Blood loss first 24 h (mL)
     
All patients
437
669
613
705
< 0.01
Open-heart procedures
431
431
707
881
< 0.01
Blood loss 48 h (mL)
     
All patients
72
159
118
223
< 0.01
Open-heart procedures
77
177
137
284
0.02
Packed red blood surgery (units)
     
All patients
0.5
1.2
0.7
1.5
0.02
Open-heart procedures
0.6
1.2
0.8
1.4
0.19
Packed red blood first 24 h (units)
     
All patients
0.7
2.1
1.3
2.4
< 0.01
Open-heart procedures
0.8
1.8
1.9
2.9
< 0.01
FFP surgery (units)
     
All patients
0.3
1.1
0.4
1.4
0.09
Open-heart procedures
0.5
1.5
0.8
1.6
0.13
FFP first 24 h (units)
     
All patients
0.8
4.4
1.6
5.0
< 0.01
Open-heart procedures
1.0
3.2
2.8
7.3
< 0.01
Platelet concentrates surgery (units)
     
All patients
0.1
0.5
0.2
0.6
< 0.01
Open-heart procedures
0.1
0.5
0.3
0.7
< 0.01
Platelet concentrates first 24 h (units)
     
All patients
0.2
0.8
0.4
1.2
< 0.01
Open-heart procedures
0.2
0.9
0.6
1.7
< 0.01
PPSB (IU)
     
All patients
14.1
154.7
30.4
186.1
0.16
Open-heart procedures
19.5
168.0
57.1
269.9
0.13
AT III (IU)
     
All patients
23.5
200.5
41.8
275.8
0.26
Open-heart procedures
30.2
237.3
38.1
237.1
0.78
F XIII (IU)
     
All patients
9.0
130.0
14.2
161.8
0.60
Open-heart procedures
11.6
120.3
23.8
244.0
0.55
aFVII (IU)
     
All patients
3.1
46.8
5.0
39.1
0.52
Open-heart procedures
3.4
36.8
13.7
65.1
0.07
Desmopressin (μg/kg)
     
All patients
0.3
2.4
0.2
1.9
0.58
Open-heart procedures
0.5
3.2
0.4
2.5
0.71
Rethoracotomy (bleeding)
      
All patients
N
13
 
23
 
< 0.01
Open-heart procedures
 
7
 
15
 
< 0.01
All patients
% in group
2.4%
 
6.9%
  
Open-heart procedures
 
3.3%
 
14.3%
  
aFVII, activated factor VII concentrate; AT III, antithrombin; FFP, fresh frozen plasma; F XIII, factor XIII concentrate; ICU, intensive care unit; PPSB, coagulation factor concentrate (prothrombin, factor VII, factor X, factor IX); OR, odds ratio; SD, standard deviation.

Subgroup with open-heart procedures

In the subgroup of patients undergoing open-heart procedures, 320 patients (105 receiving TXA and 215 receiving aprotinin) were analyzed. In this group, patients receiving TXA had significantly higher preoperative creatinine (1.31 ± 1.03 mg/dL versus 1.14 ± 0.46 mg/dL; P = 0.04) and again significantly lower levels of hemoglobin (12.5 ± 1.8 mg/dL versus 13.2 ± 1.9 mg/dL; P > 0.01).
Patients with open-heart procedures receiving TXA had increased duration of surgery (235 min ± 79 versus 210 min ± 65; P > 0.01); however, no difference between duration of CPB and aortic cross-clamping time and no difference between EURO score, APACHE II, and SAPS score on admission to the ICU was detectable (Table 2). The type of surgery, type and duration of treatment with vitamin K antagonists, clopidogrel and aspirin, as well as other comorbidities did not differ between both groups.
Patients with open-heart procedures in the TXA group showed a trend for prolonged need of mechanical ventilation (83.0 h ± 263.6 versus 36.3 h ± 188.4; P = 0.07. However, in this subgroup, no significant difference regarding duration of ICU treatment and hospital stay was detectable (Table 2).
Analysis of biochemical safety data is shown in Table 3. In this subgroup, an increase of creatinine in patients receiving TXA immediately after surgery was seen (1.30 mg/dL ± 0.73 versus 1.08 mg/dL ± 0.50; P < 0.01). The WBC, PT ratio, and aPTT were slightly different between both groups (Table 3). Acute renal failure was identical between groups (9.8% aprotinin versus 13.3% TXA; P = 0.35). However, acute renal failure was seen more often in patients receiving TXA (20.0%) compared with patients receiving aprotinin (11.2%; P = 0.04).
Even if patients with open-heart procedures receiving aprotinin did not show a significant higher rate of events of ischemic stroke (4.2% versus 1.0%; P = 0.12), we detected a higher rate of late neurologic disability (7.0% versus 1.0%; P = 0.03). The rate of postoperative convulsive seizures was increased in patients receiving TXA (6.7% versus 1.9%; P = 0.04) compared with patients treated with aprotinin. No difference regarding intracerebral hemorrhage and acute renal failure was observed. A slight increase in the rate of myocardial infarction was seen in patients receiving TXA (Table 4).
Notably, in patients with open-heart procedures, in-hospital mortality was more than twofold increased in patients receiving TXA (16.2% TXA versus 7.5% aprotinin; P = 0.02). The leading cause of death was thromboembolic events (21 of 38 deaths) in patients receiving TXA compared with the aprotinin group (11 of 29 deaths). In the multivariate backward stepwise logistic regression, aprotinin as antifibrinolytic, higher EURO score II, and prolonged CPB time were identified as independent risk factors for the excess mortality in the open-heart procedures group (Table 6).
Table 6
Multivariate backward stepwise logistic regression analysis of the increased mortality in open-heart procedures
  
B
SE
Sig.
Odds ratio (OR)
95.0% CI for OR
      
Lower
Upper
Step 1
Age
-0.043
0.018
0.019
0.958
0.924
0.993
 
CPB time
0.012
0.004
0.002
1.012
1.004
1.020
 
EURO Score II
0.278
0.063
0.000
1.321
1.168
1.493
 
Creatinine preop
0.146
0.207
0.481
1.157
0.772
1.734
 
Hemoglobin preop
-0.148
0.125
0.238
0.863
0.675
1.103
 
Antifibrinolytic
-0.788
0.437
0.071
0.455
0.193
1.070
 
Constant
-0.940
1.959
0.631
0.391
  
Step 2
Age
-0.041
0.018
0.023
0.959
0.926
0.994
 
CPB time
0.012
0.004
0.001
1.012
1.005
1.020
 
EURO Score II
0.276
0.062
0.000
1.318
1.167
1.489
 
Hemoglobin preop
-0.175
0.119
0.142
0.840
0.665
1.060
 
Antifibrinolytic
-0.832
0.431
0.054
0.435
0.187
1.013
 
Constant
-0.534
1.866
0.775
0.586
  
Step 3
Age
-0.044
0.018
0.014
0.957
0.923
0.991
 
CPB Time
0.011
0.004
0.003
1.011
1.004
1.019
 
EURO Score II
0.300
0.060
0.000
1.350
1.200
1.518
 
Antifibrinolytic
-0.947
0.424
0.025
0.388
0.169
0.890
 
Constant
-2.554
1.302
0.050
0.078
  
CI, confidence interval; CPB, cardiopulmonary bypass; OR, odds ratio; SD, standard deviation; SEM, standard error of the mean.
With regard to the efficacy of antifibrinolytic therapy, open-heart procedures being treated with TXA showed increased cumulative drainage losses at 6, 24, and 48 h after surgery (Figure 2b; Table 5) compared with patients receiving aprotinin (Pgroups < 0.01; Ptime < 0.01; Pintact < 0.01) and did receive significantly more packed red blood cells (PRBCs), units of fresh frozen plasma (FFP), and platelet concentrates (PCs) (Figure 3b). Again, the aprotinin patients had a decreased risk of being transfused with PRBCs (P < 0.01), units of FFP (P < 0.01), and PC (P < 0.01) (Figure 3b; Table 5). The need for repeated thoracotomy for bleeding in patients receiving TXA was almost 5 times higher (14.3% versus 3.3%; P < 0.01) compared with aprotinin-treated patients (Table 5).

Discussion

The two major findings of our study are as follows: first, in the overall cardiac surgery population studied, the administration of high-dose TXA showed a strong trend toward an association with convulsive seizures, whereas aprotinin was associated with a higher rate of stroke and neurologic disability after cardiac surgery with CPB. Second, in patients undergoing open-heart cardiac surgery treated with TXA, an increased mortality and a significant increase in convulsive seizures compared with patients receiving aprotinin was observed.
At our institution, aprotinin has been used for many years as the primary antifibrinolytic in patients undergoing cardiac surgery with CPB. Several studies and meta-analyses showed its superiority compared with other antifibrinolytic drugs, especially in high-risk patients undergoing cardiac surgery [8, 1214]. However, is has been criticized that the safety profile of aprotinin was not thoroughly investigated [13]. Early reports linked its use with a higher incidence of graft occlusion after CABG surgery and renal failure [15, 16]. Recently the use of aprotinin was associated with a significantly increased risk for renal failure, myocardial ischemia, stroke [1], and an impaired 5-year mortality [2]. In comparison, the same studies suggested TXA to be the safer choice of antifibrinolytic treatment. So far, only a few studies and case reports have reported the safety profile of TXA [3, 17].
Our results support an association between convulsive seizures and the use of TXA, and especially patients undergoing open-heart procedures seem to be at risk. This supports recent data from the literature indicating an increased rate of seizures in patients receiving TXA for open-heart surgery (7.9% compared with 1.2% (P < 0.01) compared with aprotinin-treated patients) [7]. Earlier case reports and experimental data indicated that TXA is linked to an epileptogenic effect if it is applied to the central nervous system [1820]. It was hypothesized that this effect might occur in part because of binding of TXA to the γ-aminobutyric acid (GABA) binding site of GABA-(A) receptors, as shown in membranes from rat cerebral cortex [21]. A recent report of Murkin et al. [9] linked the use of TXA to seizures. In two separate centers, they observed a notable increase in the incidence of postoperative convulsive seizures from 1.3% to 3.8% in patients having undergone major cardiac surgical procedures. These events were temporally coincident with the introduction of high-dose TXA therapy after discontinuation of aprotinin from general clinical use. They concluded that use of high-dose TXA in older patients in conjunction with cardiopulmonary bypass and open-heart cardiac surgery is associated with clinical seizures in susceptible patients [9].
Furthermore, we could show an association between renal failure and treatment with TXA. This could be an effect of the increased blood loss, need for transfusion, and need of repeated thoracotomy. All these factors have been linked to unfavorable outcomes in cardiac surgery patients [22, 23]. Conversely, this finding is surprising, as the use of TXA was associated with a better renal outcome in previous studies [1, 3].
Our findings that patients receiving aprotinin had a more than threefold higher rate of ischemic stroke and neurologic disability are in line with those of previous studies [1]. One hypothesis for explanation of the impaired neurologic outcome with aprotinin may be the occurrence of microvascular thrombosis, as described by Sundt et al. [24], who reported platelet-fibrin thrombi among multiple vessels, including the cerebral arteries, on postmortem examination of patients who had received aprotinin. These results confirm earlier results from observational or recent retrospective studies [1, 2], but are in contrast with results that report no difference in the incidence of stroke for aprotinin in cardiac surgery [3, 10, 25]. This might well be explained by the fact that the rates of ischemic stroke in the TXA group were low. Another German center reported a stroke rate for open procedures of 7.4% [26]. The McSPI dataset suggests that patients having combined CABG/valve replacement had permanent neurologic deficit in about 8% [27]. Therefore, the observed neurologic deficit rate for aprotinin might be about as expected.
However, also for TXA, an association with a thromboembolic risk must be hypothesized, as the leading cause of death in the group of patients treated with TXA was thromboembolic.
Our result that patients treated with TXA had increased cumulative drainage loss compared with patients receiving aprotinin is in accordance with previous studies and meta-analysis [8, 1214, 28, 29]. It has been shown that aprotinin is superior to TXA in reducing postoperative blood loss. One explanation for this may be its potential to inhibit plasmin, the final enzyme of fibrinolysis [30]. Our results confirm that the total number of transfusions and the risk of being transfused were significantly lower in the aprotinin group, as shown by others [14]. The increased bleeding might be responsible for the longer duration of surgery to achieve surgical hemostasis. Furthermore, the increased blood loss could explain in part the somewhat prolonged ventilation and the trend for prolonged hospital stay in patients receiving TXA.
The increased bleeding seen in our patients receiving TXA explains the significantly higher rate of patients transfused with PRBC, FFP, and PC. This was observed in the general patient population and was even more pronounced in patients with open-heart procedures. More than two thirds of patients undergoing open-heart procedures in the TXA group received allogenic PRBC transfusion. In line with this finding is the significantly increased rate of repeated thoracotomies in the TXA group. As bleeding and reoperation for bleeding has a major impact on outcome, this increased bleeding and need for transfusion, as well as the increased rate for reoperation seen in TXA patients, might in part be also responsible for the increased mortality seen in the TXA open-heart procedures subgroup [23].
The results of our study are in line with recent data [10] indicating that, compared with TXA, the safety profile of aprotinin is better in high-risk cardiac surgery patients. It seems that increased bleeding is associated with a higher risk of complications and mortality after cardiac surgery [23]. Although the effect of aprotinin on mortality is still considered controversial [6, 7], an increased mortality might be found in high-risk patients treated with TXA compared with aprotinin-treated patients [10]. These results might indicate a beneficial risk/benefit profile for aprotinin in certain high-risk patients, like those with open-heart procedures analyzed in our study [10].
The strengths of our study include the clinically real-world, unselected nature of the patient population and the prospective and unbiased data collection of patients receiving TXA being treated at a single center. Another strength is that in this study, no crossover between groups requiring some sort of propensity score matching was possible, as aprotinin is no longer available. However, obviously, this study also has all methodologic limitations of a retrospective study with regard to the aprotinin patients. Nonetheless, as we changed our routine practice on July 1, 2006, standard operating procedures in regard to treating cardiac surgical patients were not changed. We had the same surgeons and the same personnel in our operating rooms, ICUs, IMCUs, and normal wards, so that supposedly did not influence our results. As we adhere on a day-by-day basis to written standard operating procedures, all perioperative procedures (anesthetic management, ICU management, transfusion guidelines, and so on) are extremely standardized. Unfortunately, it was not possible to include 260 patients undergoing redo surgery, as all of these patients received aprotinin at that time as part of our standard operating procedures. Therefore, at this time from our own data, we cannot comment on whether aprotinin or tranexamic acid is superior in redo surgery. Although all the deaths were clinically adjudicated in our trial, without detailed investigations like invasive diagnostic or autopsies, a potential source of error remains.

Conclusions

The association between higher mortality and the minor efficiency of TXA questions the routine administration of high-dose TXA in cardiac surgery. In particular, our finding of the more than twofold increased mortality in patients undergoing open-heart procedures receiving tranexamic acid is worrying. However, our results confirm also that aprotinin is associated with severe neurologic adverse reactions. The safety profile of antifibrinolytic treatment--aprotinin and TXA--warrants further evaluation to answer the question whether the benefit of this treatment outweighs its potential risks. For the future, controlled trials investigating the safety profile of antifibrinolytic therapy are needed. With regard to TXA, the effective and safe dosage as well as the patients who will most likely benefit from this medication must be established.

Key messages

  • The association between higher mortality and the minor efficiency of tranexamic acid questions the routine administration of high-dose tranexamic acid in cardiac surgery. In particular, our finding of the more than twofold increased mortality in patients undergoing open-heart procedures receiving tranexamic acid is worrying.
  • Aprotinin and tranexamic acid were associated with neurologic adverse reactions in this retrospective study.
  • The safety profile of antifibrinolytic treatment--aprotinin and tranexamic acid--warrants further evaluation to answer the question whether the benefit of this treatment outweighs its potential risks.

Acknowledgements

The authors appreciate the diligent help from Dipl.-Math. Mrs. Gerda Siebert (Department of Medical Biometry, Charité University Medicine Berlin, Germany) with the acquisition of the data as well as for the detailed statistical advice for analyzing the data.

Competing interests

The authors declare that they have no competing interests. This work was supported by institutional grants from Charité-Universitätsmedizin, Berlin, Germany.

Authors' contributions

MS and CvH prepared the manuscript, conceived the study, and performed the statistical analysis. MS, CvH, and VM carried out the data acquisition; KDW prepared the statistical part of the manuscript and performed the statistical analysis. CR and CS drafted the manuscript and helped with the study design and coordination. All authors read and approved the final manuscript.
Zusatzmaterial
Authors’ original file for figure 1
13054_2010_8623_MOESM1_ESM.tiff
Authors’ original file for figure 2
13054_2010_8623_MOESM2_ESM.jpeg
Authors’ original file for figure 3
13054_2010_8623_MOESM3_ESM.jpeg
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