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ORIGINAL ARTICLE
Ahead of print publication  

Comparison of effectiveness and safety of epsilon-aminocaproic acid and tranexamic acid in adult patients undergoing cardiac surgery


1 Department of Anaesthesia, RIMS, Imphal, Manipur, India
2 Departments of Anaesthesiology and Intensive Care, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana; Department of Cardiac Anaesthesia, SAMSRI, Lucknow, Uttar Pradesh, India
3 Departmentof Surgery, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
4 Department of Cardiac Anaesthesia, SAMSRI, Lucknow, Uttar Pradesh, India
5 Department of Community Health, School of Public Health, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Date of Submission25-Dec-2021
Date of Decision24-Feb-2022
Date of Acceptance17-Apr-2022
Date of Web Publication23-Jun-2022

Correspondence Address:
Sanjeev Singh,
Department of Anaesthesiology and Intensive Care, Kwame Nkrumah University of Science and Technology, Kumasi

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jms.jms_149_21

  Abstract 


Objective: The objective of the study is to evaluate the effectiveness and safety of epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) in reducing bleeding, re-exploration, and blood transfusion in patients who underwent a cardiac surgical procedure for mitral valve replacement on cardiopulmonary bypass.
Methods: A single-center, prospective, randomized, and double-blind clinical comparison study was conducted after obtaining institutional ethical approval; sixty patients of either gender between 18 and 60 years of age were randomly divided into two batches: EACA batch (n = 30) given 100 mg/kg EACA as a bolus during induction of anesthesia and then infused at 20 mg/kg/h during surgery and 6 h after surgery and TXA batch (n = 30) given TXA 20 mg/kg/h as a bolus during induction of anesthesia and then infused at 2 mg/kg/h during surgery and 6 h after surgery. The patient parameters, blood loss, transfusion requirements in the first 24 h, and other complications were recorded.
Results: Blood loss per hour through the chest tube drain was significantly lower for the first 6 postoperative hours in the TXA than in the EACA (P < 0.05). The total postoperative blood loss was 416 ± 47.74 ml and 489 ± 42.12 ml in 24 h (P = 0.0001), and the blood transfusion requirement was 0.45 ± 0.62 units and 0.86 ± 0.87 units (P = 0.0481) in the TXA and EACA, respectively. The re-exploration rate was 3.34% and 13.34% in TXA and EACA (P = 0.0629). Five percent of the patients reported seizures in the study (P > 0.05). The findings of this study suggested that prophylactic therapy with EACA or TXA was effective and safer in reducing perioperative blood loss in cardiac surgical procedures with mitral valve replacement. Furthermore, TXA was significantly more effective than EACA.

Keywords: Bleeding, cardiac surgery, epsilon-aminocaproic acid, tranexamic acid



How to cite this URL:
Singh LC, Singh S, Okyere I, Annamalai A, Singh A. Comparison of effectiveness and safety of epsilon-aminocaproic acid and tranexamic acid in adult patients undergoing cardiac surgery. J Med Soc [Epub ahead of print] [cited 2022 Jul 3]. Available from: https://www.jmedsoc.org/preprintarticle.asp?id=348016




  Introduction Top


Most corrective cardiac surgeries are impossible without cardiopulmonary bypass (CPB). Nonendothelial areas of the CPB circuit cause contact activation of the coagulation cascades and platelets. The volume of prime CPB results in significant hemodilution. Thus, CPB leads to increased fibrinolysis, a decreased platelet number or function, and dilution of clotting factors. Colson et al. reported active bleeding in patients with heart surgery of up to 16%.[1] Dixon et al. supported these findings and reported that 8%–93% of patients required blood or blood component transfusion in data from 798 surgical units.[2] Bleeding after cardiac surgery is a well-known complication, which increases the re-exploration rate, blood transfusion requirement, length of stay (LOS) in the hospital, and cost.[3] Every effort should be made to prevent and control bleeding after surgery. Prophylactic antifibrinolytic therapy is one approach to reduce postoperative bleeding. At present, the commonly available antifibrinolytics are epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) for use. The aprotinin was one of the extensively evaluated antifibrinolytic agents.[4] The Blood Saving Using Antifibrinolytics in Randomized Controlled Trial (BART) study showed an increased risk of allergic reaction and thrombosis[5]-related risk of death[6] with aprotinin, limiting its use in situations that verify the benefit.[7] An alternative to aprotinin is EACA, a synthetic and inexpensive antifibrinolytic. EACA inhibits the binding of plasmin to fibrin by occupying the lysine-binding sites of the proenzyme plasminogen. With no activation of plasmin, there is a reduction in fibrinolysis.[8] EACA is a recommended antifibrinolytic in the guidelines of multiple anesthesiology societies and task forces.[9],[10] Another synthetic antifibrinolytic is TXA which is cheaper and acts like EACA but is ten times more potent.[5] TXA stabilizes the endothelial glycocalyx of blood vessels,[11] attenuates the inflammatory responses in patients undergoing on-pump surgery,[12] and suppresses the release of mitochondrial damage-associated molecular patterns.[13] A literature search revealed variable results in patients with EACA and TXA use in open-heart surgery patients. Some studies do not show any difference, while others indicate that EACA is a more potent blood-sparing agent than TXA.[14],[15] However, some literature highlights the possible adverse side effects of TXA, such as seizures and renal dysfunction.[16],[17] Our study directly evaluated TXA and EACA without comparison with a placebo since the efficacy of antifibrinolytic drugs has been established in the literature,[18],[19] so it is unethical to conduct a placebo control study. We evaluated the effectiveness rather than the efficacy of using EACA and TXA. EACA and TXA are readily available, inexpensive, and synthetic antifibrinolytics chosen for this study. This study aimed to compare the effectiveness of EACA and TXA in reducing bleeding, re-exploration, transfusion requirements, and adverse effects in cardiac surgery patients undergoing mitral valve replacement surgery on CPB.


  Methods Top


Objective of the study

This study aims to compare the blood loss, blood transfusion, re-exploration, and adverse outcomes in mitral valve replacement surgery patients administered either EACA or TXA.

Study design

A single-center, prospective, randomized, and double-blinded clinical comparison study was conducted after approval by the Committee on Human Research Publications and Ethics No: 254 ANS/SAMSRI/CHRPE/2017-18 in 2017. Informed consent was obtained from all 60 patients after explaining the study protocols.

Study participants

Inclusion criteria for the study were the American Society of Anesthesiologists (ASA) physical status II and III, adult male and female between the age of 18 and 60 years, scheduled for elective on-pump surgery to replace the mitral valve under general anesthesia, hematocrit >30%, preoperative hemoglobin (Hb) >10 g%, normal coagulation profile including PT, and international normalized ratio (INR). Exclusion criteria for the study were morbidly obese (body mass index [BMI] ≥30 kg/m2), ASA >III, SBP <100 mmHg, heart rate <50 beats/min, allergic reaction to antifibrinolytic drugs, bleeding diathesis, thrombosis, urinary tract bleeding, kidney failure (serum creatinine >2), pregnancy, emergency surgery, redo surgery, a patient treated with antiplatelet within 7 days of surgery, deranged coagulation profile PT <75% or INR >2, and patient refusal.

Study variables

In this study, the independent variables were sociodemographic and operative data (age, sex, height, weight, BMI, etc.). The dependent variables were changes in heart rate, systolic blood pressure, diastolic blood pressure, central venous pressure, urine output, duration of surgery, duration of CPB, activated clotting time (ACT), Hb, platelet count, blood loss postoperative, and units of blood and blood components transfused.

Determination of the sample size

The sample size was calculated using an online calculator – sample size (n) = Z2pq/d2, where z= Standard score corresponds to a confidence level of 95%, P = estimated proportion (referenced from the previous study) and d = precision or tolerance margin of error, with alpha and beta set at 5% and 20%, respectively. The following assumptions were considered to estimate the sample size required for the study. A confidence interval of 95% and power of 80% were deemed adequate. From the previous studies, the mean ± standard deviation in the tranexamic acid group was 440 ± 230 ml, while in the control group, it was 660 ± 180. Pugh used antifibrinolytic drugs to reduce perioperative blood transfusion requirements in patients with cardiac surgery.[20] The incidence of bleeding in patients who received antifibrinolytic agents was 17% compared to 31% of patients who did not receive antifibrinolytic agents. A sample size of 25 patients is needed for each group, and adding 10% of the dropout makes the total sample size 60 (30 subjects/group).

Determination of the sampling technique

The daily operation schedule list from operation theaters was used as a sampling frame. Sixty study subjects were selected from the theater manager's surgical caseload. A balloting system with “Yes” and “No” was used to choose at the point of recruitment. After reviewing 218 patients, who met the eligibility criteria, those who picked YES were enrolled until the sample size was reached. The patients were then divided into two batches with the help of a computer-generated randomization program.

Person “A” prepared theater drugs, anesthetized patients, and managed patients in the intensive care unit (ICU), Person “B” was involved in the blinding process and preparation of study drugs, while Person “C” was responsible for patient intraoperative and ICU records. As a result, persons “A” and “C” and the patient were kept unaware of the study drug used to enable double blinding.

Presurgical protocol

The day before surgery, patients underwent preanesthetic evaluation with special consideration to detect any new changes. Information collected included weight, nutritional status, a detailed airway, and cardiovascular and central nervous system examination. In addition, routine preoperative investigations including total lymphocyte count, differential lymphocyte count, Hb, hematocrit, blood group/Rh typing, serum electrolytes, blood urea nitrogen, serum creatinine, X-ray chest, electrocardiogram, and echocardiogram of the heart were checked as per protocol. Patients were advised to fast the night before surgery.

Surgical protocol

After receiving the patient in the operating room, documents were re-checked, a brief clinical examination was performed, and standard monitors were attached, including pulse oximetry, electrocardiogram, noninvasive blood pressure (NIBP) monitoring, and temperature probe. Baseline parameters such as heart rate, rhythm, NIBP monitoring, SpO2, and respiratory rate were monitored before induction of anesthesia. A peripheral intravenous line was established with a 20G cannula, and Hartmann's solution was started. Premedication with injection (inj.) fentanyl 3 μg/kg and inj. midazolam 0.05 mg/kg, the patient was pre-oxygenated with 100% oxygen for 2 minutes and then induced anesthesia with inj. thiopental 5–7 mg/kg. Neuromuscular blocking was achieved and maintained with inj. vecuronium 0.15 mg/kg. The patient was intubated with the appropriate sized cuffed endotracheal tube and ventilated. Anesthesia was maintained with isoflurane 0.6%–1.5% in a semi-closed circle system with a CO2 absorber and a flow rate of 3 L/min on the Datex Ohmeda anesthesia machine. Radial arterial and central venous lines were established for invasive blood pressure (IBP) and central venous pressure (CVP). IBP and CVP were monitored throughout surgery and postoperatively. The study drugs were administered according to the study protocol by the anesthetist. Inj. fentanyl, midazolam, and vecuronium were administered as per patient requirements. Inj. heparin 300 U/kg was administered to maintain ACT >400 s on CPB and supplemented as necessary. The pump prime consisted of 1200 ml of electrolyte solution, 5000 units of heparin, 500 ml of tetrastarch-containing 25 meq of sodium bicarbonate, 100 ml of mannitol, and Lasix 1 mg/kg. The CPB was maintained by a roller pump using a membrane oxygenator. On CPB, the patient underwent standard nonpulsatile normothermic or mild hypothermic (27°C–31°C). When the patient was off-pump at the end of the surgery, heparin was neutralized with protamine. Blood samples were collected for arterial blood gas (ABG), Hb, and electrolytes after induction, immediately after heparin administration, after neutralization with protamine, postoperatively at 1, 2, 3, 4, 5, 6, 9, 12, 18, and 24 h. ACT was performed after heparin administration, after protamine titration, and if the bleeding was >200 ml/h. The patients were transferred to the cardiac care unit and mechanically ventilated for 4–5 h before extubation. Removal of the endotracheal tube after ensuring hemodynamic stability, temperature 36°C, no active bleeding, and sufficient spontaneous ventilation indicated by Tidal volume (Vt) >6 ml/kg.

Parameters and statistical analysis

The demographic statistics of the patient and the effects of antifibrinolytics on blood loss and blood transfusion requirements were presented as mean and standard deviation of blood loss, Hb, and packed red blood cell units transfused for each trial drug. Data for continuous parameters were collected and compared. Statistical analysis was performed using an unpaired t-test, while nonnormalized data were compared using the Mann–Whitney test. The P < 0.05 was considered statistically significant. Data analysis was performed using Stata/SE 13.1 statistical software (StataCorp LP Statistics/Data Analysis StataCorp 4905 Lakeway Drive Special Edition College Station, Texas 77845 USA 800–STATA–PC http://www.stata.com, [email protected]).


  Results Top


A total of 621 cases were reviewed, and of these, 218 patients met the inclusion criteria. Sixty were randomly selected for the study. The mean age of the EACA batch was 32.43 ± 11.81 years compared to that of the TXA batch (29.38 ± 10.35 years); no significant differences were observed with P = 0.2846. The male-to-female ratio of EACA was 1:1.73, and TA was 1:2 with P = 0.3443. The mean weight and height were 43.52 ± 6.89 kg and 42.94 ± 12.53 kg with P = 0.8161 and 155.86 ± 11.05 cm and 153.02 ± 12.70 cm with P = 0.5324 in the EACA and TXA batches, respectively. The average body mass index was 17.98 ± 1.90 kg/m2 and 18.04 ± 3.49 kg/m2 with P = 0.6252 in the EACA and TXA batches, respectively. Both the batches were comparable in demographic profile, as shown in [Table 1].
Table 1: Distribution of the demographic profile of the patient in the study batches

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No significant differences were observed in the clinical characteristics, as shown in [Table 2]. Baseline Hb, platelets, INR, renal function test, and CPB duration were statistically insignificant for EACA and TXA (P > 0.05). Also, the baseline ACT, post heparin ACT, and after protamine titration ACT was insignificant in both the groups with P > 0.05.
Table 2: Clinical characteristics of the study population

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Blood loss and parameters were recorded according to the study protocol. Blood loss was recorded at 1, 2, 3, 4, 5, 6, 9, 12, 18, and 24 h. Blood loss at a specified interval in each batch is shown in [Table 3]. The mean blood loss recorded at 1, 2, 3, 4, 5, and 6 h was significantly higher in the EACA than in the TXA. After 6 h, although the mean blood loss was higher in the EACA, the difference was not statistically significant. The total chest drain in 24 h was 489.03 ± 42.12 ml in the EACA and 416.05 ± 47.74 ml in the TXA, which was significantly higher in the EACA group (P < 0.05) in [Table 3].
Table 3: Comparison of mean postoperative blood loss in 24 h

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The number of units of whole blood transfused in the TXA was 0.45 ± 0.62 and the EACA was 0.86 ± 0.87 units; there was a significant decrease in the unit of blood transfused in the TXA (P = 0.0481), as shown in [Table 4]. The number of units of FFP and platelets required per patient did not vary significantly among the two batches. The re-exploration rate was 13.33% and 3.33% in the EACA and TXA batches, respectively, and the rate of re-exploration was comparable between the two batches (P > 0.05).
Table 4: Comparison of units of blood and blood components transfused in the study batches

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The patients' mean Hb in the EACA and TXA batches was comparable at baseline, pre-CPB, post-CPB, 1 h, and 18 h after surgery. At 24 h, Hb was 9.95 ± 1.16 in EACA and 10.74 ± 1.23 in TXA, which improved statistically significantly in the TXA group (P = 0.0139), as shown in [Table 5].
Table 5: Comparison of mean hemoglobin in study groups

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In our study, platelet count was recorded at hourly intervals of 1, 2, 3, 4, 5, and 6 h and then at 9, 12, 18, and 24 h. Mean platelet counts in both the batches are shown in [Table 6] at specified intervals. Mean platelet counts were comparable between the EACA and TXA batches (P > 0.05).
Table 6: Comparison of the mean platelet count in study batches

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The postoperative mechanical ventilator support duration was 12.37 ± 2.42 and 11.82 ± 1.76 h in EACA and TXA, respectively, which was comparable. The average LOS and the average hospital LOS were 46.41 ± 7.46 and 28.52 ± 5.48 and 147 ± 6.72 and 97.73 ± 8.52 hours in the batches of EACA and TXA, respectively. LOS in the ICU was statistically significantly low for TXA.

In the first 24 h, postoperative chest tube drainage was significantly less in TXA 416.05 ± 47.74 than EACA 489.03 ± 42.12 (P = 0.001). Seizures were reported in three patients representing 5% of the study population. A patient in the EACA batch and two patients in TXA reported seizures, which was statistically insignificant (0.741), as shown in [Table 7]. No other adverse complication was reported in either batch, such as renal failure, stroke, or acute myocardial infarction.
Table 7: Comparison of clinical variables in study batches

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  Discussion Top


Massive bleeding is one of the common life-threatening complications associated with cardiothoracic surgery. It has inevitable consequences such as increased re-exploration, transfusion requirements, and multiple organ dysfunctions due to impaired perfusion and oxygenation. Prophylactic antifibrinolytic therapy during cardiac surgery reduces blood loss and the need for blood transfusion.[4],[5],[8] The most thoroughly evaluated antifibrinolytic agent in cardiothoracic surgery was aprotinin. Its effectiveness in reducing postoperative bleeding was established in more than forty clinical trials and two meta-analyses.[4] However, there were concerns about possible allergic reactions and thrombosis-related side effects with aprotinin.[5] Following the publication of the “BART” study in 2007, Bayer removed the marketing of aprotinin from the market. The BART study showed an increased risk of death with aprotinin.[6] Under the limited use agreement, aprotinin in cardiothoracic surgery is limited to the situation that verifies that the benefits of antifibrinolytic aprotinin outweigh the risks.[7],[20] There are little data to directly compare the efficacy of the remaining two antifibrinolytics, TXA and EACA.[14],[15],[19] TXA is a commonly used antifibrinolytic worldwide. EACA was used in a few European countries and the United States.[18] EACA was used in our hospital for this study to compare the effectiveness of EACA and TXA. There is little evidence to support one antifibrinolytic better than another in reducing transfusion requirements and blood loss.

Falana and Patel performed a retrospective study on 120 cardiovascular surgery patients who received at least one dose of TXA or EACA. The authors concluded that TXA and EACA do not have differences in efficacy.[15] This variation from our result was probably due to the study design, as it involved both on- and off-pump cases and different doses of antifibrinolytics used in two studies.

One of the most common concerns associated with antifibrinolytic drugs is the increased risk of seizures.[17] The incidence of seizures was reported by Makhija et al. in the TXA batch but was not statistically significant.[21] Our findings match the findings of Makhija et al. with 3.3% and 6.7% seizures in the EACA and TXA batches, respectively (P = 0.7415). Because our study was underpowered for the rare outcome of seizures, we could not draw any conclusions regarding the risk of seizures in those patients treated with EACA or TXA. In contrast to our results, Martin et al. reported a significantly higher rate of seizures in patients treated with TXA.[16] It is worth noting that Martin et al. patients were exposed to high doses of TXA (2 g at the beginning of CPB and then 0.5 g/h as a continuous infusion until chest closure and 2 g was added to the prime of the CPB equipment). However, the manufacturer's package inserts mention that TXA may cause focal and or generalized seizures.

Due to the concerns of seizures or renal dysfunction with antifibrinolytic, we used safe doses of EACA and TXA from the literature. Harrow et al. in a TXA dose–response study reported that chest tube drainage was lower with a dose of 20 mg/kg followed by 2 mg/kg/h compared to 10 mg/kg followed by 1 mg/kg/h[22]; therefore, we used 20 mg/kg followed by 2 mg/kg/h for the TXA batch. This dose of TXA was much lower than the dose used by Martin et al.[16] EACA 100 mg/kg body weight bolus and then infusion 20 mg/kg/h maintains blood EACA concentrations at or above 260 mg/L reported in the literature.[23] This dose of EACA was safe and effective in reducing blood loss, as reported by Dowd et al.[23] Therefore, we used EACA 100 mg/kg body weight bolus and then infusion 20 mg/kg/h.

The postoperative mechanical ventilator support duration was 12.37 ± 2.42 and 11.82 ± 1.76 h in EACA and TXA, respectively, which were not significantly lower for TXA in our study. Although Broadwin et al. in 2020 reported that ventilator support was less needed in the TXA group, their findings were significant,[24] possibly due to the fast-track extubation protocol in their hospital. The average ICU LOS was 46.41 ± 7.46 and 28.52 ± 5.48 h in our study's EACA and TXA batches, respectively, which was statistically significantly low for TXA (P = 0.0427). In contrast to our results, Broadwin et al. found no significant difference in the two groups in LOS. We recorded and compared hourly chest tube drainage for 24 h, but Broadwin et al. compared at specific intervals. Our institution's intensive monitoring and enhanced recovery after surgery (ERAS) protocols allowed us to achieve this result. ERAS management reduces anesthesia and hospital-related complications through evidence-based medicine in the ICU.[25]

In our study, the mean total postoperative blood loss was 416 ± 47.74 ml and 489 ± 42.12 ml (P = 0.0001) in the first 24 h in the TXA and EACA groups, respectively. These results concur with Leff et al. study in 2019, in which they compared the effectiveness of TXA and EACA in decreasing blood loss and transfusion requirements in patients undergoing cardiothoracic surgeries. However, their study did not report statistically significant differences between the two groups when analyzing blood loss. Nevertheless, they found a significant difference in the blood transfusion requirement in 24 h postoperatively, with less transfusion in patients receiving EACA than TXA (25% vs. 44.8%, respectively; P = 0.027) in contrast to our results.[14] In our study, 0.45 ± 0.62 units and 0.86 ± 0.87 units of blood were transfused in 24 h, which was significantly lower in TXA (P = 0.0481); this was maybe due to the different doses of TXA used in the two studies and the heterogeneity of the sample population. In addition, we used MVR cases for both the study groups, while Leff et al. selected MVR and CABG cardiac surgery cases in different proportions for the EACA and TXA groups.


  Conclusions Top


The findings of this study suggest that TXA is significantly effective in reducing postoperative blood loss in the first 24 h and blood transfusion requirement. The incidence of seizures was not significantly similar between the two groups. Our results suggest that TXA is more effective than EACA.

Limitations

This is a single-center study; the generalization of the study findings will be finite. We need to conduct a multicentric trial with a large sample size to generalize the result. The plasma levels of EACA were not checked to detect its therapeutic levels in our study. There exist many dosing regimens for both EACA and TXA. We could extend this study to other dosing regimens to compare the results of different doses. However, our institution adheres to restrictive transfusion practices. Administration of blood is based on a Hb level <8 g/dl or hemodynamic instability on the request of the anesthesiologist with ongoing bleeding.

Data availability

The data are available in the manuscript. The data sets used and analyzed during the current study are available from the corresponding author on a reasonable request.

Ethical approval

This study was approved by the Ethical Clearance Committee on Human Research SH/09 1/N/2017-18 of SAMSRI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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[PUBMED]  [Full text]  
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

 
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  In this article
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
Article Tables

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