BEST EVIDENCE TOPIC – ADULT CARDIAC

Interactive CardioVascular and Thoracic Surgery 21 (2015) 384–388 doi:10.1093/icvts/ivv134 Advance Access publication 25 May 2015

Cite this article as: Hodgson S, Larvin JT, Dearman C. What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Interact CardioVasc Thorac Surg 2015;21:384–8.

What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Sam Hodgson*, Joseph T. Larvin and Charles Dearman Department of Medical Sciences, University of Oxford, Oxford, UK * Corresponding author. St John’s College, Oxford OX1 3JP, UK. Tel: +44-7939-081096; fax: +44-7939-081096; e-mail: [email protected] (S. Hodgson). Received 16 January 2015; received in revised form 8 April 2015; accepted 5 May 2015

Abstract A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Altogether 586 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Current evidence shows clinical benefit of using high-dose tranexamic acid (>80 mg/kg total dose) as opposed to low-dose tranexamic acid ( 0.05)

30-day mortality (%)

Low-dose 3.9 vs moderate-dose 4.8 vs high-dose 4.2 (P > 0.05)

175 patients undergoing cardiac valve surgery on CPB

Blood loss during day 1 (ml)

Low-dose 540 vs high-dose 495 (P = 0.24)

Low-dose: 88 patients, 10 mg kg−1 bolus + 2 mg kg−1 h−1 + 40 mg priming dose before bypass

Patients requiring red blood cell transfusion

n = 48 low-dose vs n = 44 high-dose (P = 0.60)

Patients requiring fresh frozen plasma transfusion

n = 30 low-dose vs n = 22 high-dose (P = 0.20)

Seizure

n = 1 low-dose vs n = 1 high-dose (P = 1.00)

Blood loss at 6 h postoperatively (ml)

Low-dose 251 ± 149 vs high-dose 232 ± 173 (P > 0.05)

Red blood cell transfusion

Low-dose n = 43 vs high-dose n = 40 (P > 0.05)

Fresh frozen plasma transfusion

Low-dose n = 10 vs high-dose n = 9 (P > 0.05)

High-dose: 285 patients, 30 mg kg−1 bolus + 16 mg kg−1 h−1 + 2 mg kg−1 priming

Waldow et al. (2013), Clin Hemorheol Microcirc, Germany [3]

1182 patients undergoing elective on-pump cardiac surgery

Prospective clinical trial (level IIa)

Low-dose: 1 g priming dose Moderate-dose: 5 g priming dose

No difference in mortality or transfusion incidence Differences in mean blood loss, mean units of blood product transfused and incidence of repeat surgery for haemostasis

Doses were varied on each surgical day, as opposed to patients being randomized

High-dose: 3 g priming dose plus weight-adjusted infusion Du et al. (2014), J Cardiothorac Vasc Anesth, China [4] Double-blinded randomized controlled trial (level 1b)

Armellin et al. (2004), Minerva Anestesiol, Italy [5] Double-blinded randomized controlled trial (level 1b)

High-dose: 87 patients, 30 mg kg−1 bolus + 16 mg kg−1 h−1 + 2 mg kg−1 priming dose before bypass

250 patients undergoing elective primary CABG Low-dose: 15 mg kg−1 bolus + 1 mg kg−1 h−1 High-dose: 30 mg kg bolus + 30 mg kg−1 priming dose

−1

No differences in blood loss or transfusion products

Continued

BEST EVIDENCE TOPIC

Double-blinded randomized controlled trial (level 1b)

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Table 1: (Continued) Author, date, journal and country; Study type (level of evidence)

Patient group

Outcomes

Key results

Comments

Faraoni et al. (2014), Eur J Anaesthesiol, USA [6]

33 patients undergoing cardiac surgery

Fibrinolysis (LY30 thromboelastography results)

Difference between high-and low-dose TA = 0.08 (95% CI −0.82 to 0.66)

No difference in fibrinolysis between high-dose and low-dose TA

Difference between high-dose TA and placebo = 0.7 (95% CI −0.04 to 1.4)

Very low numbers of participants, poorly powered

Double-blind randomized controlled trial [pilot] (level 1b)

Low-dose: 5 mg kg−1 bolus + 5 mg kg−1 h−1 −1

High-dose: 30 mg kg bolus + 16 mg kg−1 h−1

Difference between low-dose TA and placebo = 0.78 (95% CI 0.02 to 1.5)

Control: NaCl

Koster et al. (2013), Br J Anaesth, Germany [7] Retrospective multivariate analysis (level III)

4883 cardiac surgical patients 1029 patients low-dose: 24 mg kg−1. Given at discretion of surgeon/anaesthetist; typical indications included active antiplatelet therapy, reoperations and complex procedures with an expected CPB time exceeding 90 min

Blood loss

No difference between groups

Transfusion requirement

No difference between groups

CS (propensity-adjusted)

Adjusted OR for CS in the TA group was 1.703 [95% CI: 1.01–2.87; P = 0.045]

ICU stay (h)

TA group 104.9 vs Reference group 66.5 (P < 0.001)

In-hospital mortality (%) (propensity-adjusted)

TA group 4.1 vs Reference group 1.5 (P < 0.001)

3854 patients reference group: No TA

Manji et al. (2011), Can J Anaesth, Canada [8] Retrospective multivariate analysis (level III) Sharma et al. (2014), Anaesthesia, Canada [9] Retrospective multivariate analysis (level III)

5958 patients undergoing cardiac surgery

In subgroup analysis, statistically significant differences between the TA and reference groups were only detected in patients undergoing open heart surgery No differences between groups were observed in patients undergoing CABG

In-hospital mortality (odds) (propensity-adjusted)

(OR = 1.89; 95% CI: 1.21–2.96; P = 0.005)

Seizure

TA use associated with an increased risk of seizures (OR = 7.4, 95% CI 2.8–19.3; P < 0.001)

Seizure patients had statistically significant higher rates of postoperative neurological complications, ICU stay and ICU mortality

Seizure

TA use independent predictor of seizure (OR = 14.3, 95% CI 5.5–36.7; P < 0.001)

All patients received preoperative lorazepam, and were cooled to 20°C

TA dose: 30 mg kg−1 + 16 mg kg−1 h−1 + or 1–2 g total dose

11 529 patients undergoing cardiac surgery with CPB

Odds of seizure adjusted for propensity

8132 patients lower dose 50 mg kg−1 bolus

Low-dose 0.3% seizure risk vs high-dose 2.6% seizure risk (P < 0.0001)

2847 patients received infusion (>80 mg kg−1 total dose)

This study does not demonstrate causality

Increased duration of hospital stay and in-hospital mortality were associated with seizures This study does not demonstrate causality

Kalavrouziotis et al. (2012), Ann Thorac Surg, Canada [10]

8929 patients undergoing CPB (High-dose TA >100 mg kg−1)

Seizure within 24 h of CPB

OR for seizure in patients receiving >100 mg kg−1 TA = 2.6 (P < 0.0001)

Pre-existing non-acute discrete lesion on brain imaging in 30% of early seizure patients

Retrospective multivariate analysis (level III)

Continued

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387

Author, date, journal and country; Study type (level of evidence)

Patient group

Outcomes

Key results

Comments

Sharma et al. (2012), Anaesthesia, Canada [11]

8 patients undergoing elective cardiac surgery with CPB

Plasma TA concentration

Higher levels than expected based on previous modelling. Plasma levels throughout surgery and up to 6 h postoperatively consistently higher than suggested to produce 100% inhibition of tissue plasminogen activator

High dose of TA used by many studies and centres is too high; sufficient inhibition of tissue plasminogen activator could be achieved at lower TA doses

Plasma TA levels

Plasma TA levels fit a 2-compartment model of TA pharmacokinetics

This high dose has been widely used since

TA plasma concentration

Low-dose 28–55 µg ml−1 vs High-dose 114–209 µg ml−1

A specific continuous high-dose infusion scheme should be used to maintain TA target concentration around 150 µg ml−1

Pharmacokinetic study (level III)

Dowd et al. (2002), Anesthiology, Canada [12] Pharmacokinetic study (level III) Grassin-Delyle et al. Br J Anaesth, France [13] Double-blinded randomized controlled trial (level 1b)

30 mg kg−1 bolus + 16 mg kg−1 h−1 infusion + 2 mg kg−1 priming dose

30 patients undergoing CPB High-dose: 30 mg kg−1 + 16 mg kg−1 h−1 + 2 mg kg−1 priming dose 61 patients undergoing cardiac surgery with CPB Low-dose: 10 mg kg−1 bolus + 1 mg kg−1 h−1 + 1 mg kg−1 priming dose High-dose: 30 mg kg−1 + 16 mg kg−1 h−1 + 2 mg kg−1 priming dose

The concentration required varies with patient body weight

CI: confidence interval; CPB: cardiopulmonary bypass; CS: convulsive seizures; OR: odds ratio; ICU: intensive care unit; CABG: coronary artery bypass graft; TA: tranexamic acid.

SEARCH OUTCOME A total of 586 papers were found using the reported search. From these, 12 papers were identified that provided the best evidence to answer the question. These are presented in Table 1.

RESULTS Sigaut et al. [2] demonstrated differences in postoperative blood loss and incidence of repeat surgery between high (30 mg kg−1 bolus + 16 mg kg−1 h−1 + 2 mg kg−1 priming) and low (10 mg kg−1 bolus + 1 mg kg−1 h−1 + 1 mg kg−1 priming) dose TA regimens in 569 adult patients on CPB for cardiac surgery. Mean blood loss in the low-dose group was 820 ml during day 1, compared with 590 ml for the high-dose group (P = 0.01). While statistically significant, the mean difference (230 ml) is small. Repeat surgery to achieve haemostasis was performed in 6.2% of low-dose patients compared with 2.5% of high-dose (P = 0.03). Subgroup analysis showed the greatest reduction in bleeding and repeat surgery was observed in patients at high transfusion risk. No differences in 7-day transfusion incidence or 28-day mortality were observed, although the amount of blood products transfused was lower in the high-dose TA group (2.5 units) than the low-dose group (4.1 units) (P = 0.02). Waldow et al. [3] conducted a larger study (n = 1182) in on-pump cardiac surgery patients and detected no statistically significant differences in blood loss, 30-day mortality, myocardial

infarction or stroke between patients receiving low (1 g priming dose), moderate (5 g priming dose) or high-dose TA (3 g priming dose plus weight-adjusted infusion). Du et al. [4] found no difference between clinical outcomes with high (30 mg kg−1 bolus + 16 mg kg−1 h−1 + 2 mg kg−1 priming dose) and low (10 mg kg−1 bolus + 2 mg kg−1 h−1 + 40 mg priming dose) dose TA in 175 patients undergoing valve surgery. Rates of blood loss, red blood cell (RBC) transfusion and fresh frozen plasma (FFP) transfusion were similar between groups. This study, however, excluded patients with renal and hepatic failure (and consequently at a higher risk of bleeding), the group for whom the greatest differences in blood loss were detected in Sigaut et al.’s study [2]. Armellin et al. [5] concluded that blood loss and transfusion rates of both RBCs and FFP were similar in 250 patients randomized to receive either high (30 mg kg−1 bolus + 30 mg kg−1 priming dose) or low (15 mg kg−1 bolus + 1 mg kg−1h−1) dose TA during coronary revascularization. Faraoni et al. [6] demonstrated no difference in clinical outcomes or fibrinolysis between high (30 mg kg−1 bolus + 16 mg kg−1 h−1) and low (5 mg kg−1 bolus + 5 mg kg−1 h−1) dose TA. With 33 patients included, this small pilot study may have been inadequately powered to detect true differences. Retrospective multivariate regression analyses by Koster et al. [7], Manji et al. [8] and Sharma et al. [9] demonstrate that TA use is associated with increased risk of postoperative seizure in patients undergoing cardiac surgery with CPB [odds ratio (OR) = 1.703, P = 0.045; OR = 7.4, P < 0.001 and OR = 14.3, P < 0.0001, respectively].

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Table 1: (Continued)

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Subgroup analysis performed by Koster et al. [7] showed that this increased risk of seizure with TA was statistically significant for open heart surgery and not for coronary artery bypass graft. Koster et al. [7] also found that TA use was associated with increased in-hospital mortality (OR = 1.89, P = 0.005). The TA group were higher risk in terms of factors including age and presence of pulmonary disease; the authors used a propensity score adjustment in their analysis. Observational data demonstrate that higher doses of TA are associated with higher seizure risk than low-dose TA. Sharma et al. [9] observed less risk of seizure in patients receiving low-dose (50 mg kg−1) than those receiving high-dose TA (>80 mg kg−1) (0.3 vs 2.6% P < 0.0001). Kalavrouziotis et al. [10], using a similar multivariate regression analysis approach, found that >100 mg kg−1 total TA dose was an independent predictor of seizure within 24 h of surgery (OR = 2.6 P < 0.0001). Evidence of pre-existing non-acute discrete lesions on brain imaging was present in 30% of these seizure patients. No prospective trials have demonstrated an association between TA and increased seizure risk. As a result, no causal relationship can be inferred from available data. Pharmacokinetic studies show that high-dose TA is not required to achieve adequate inhibition of fibrinolysis. Sharma et al. [11] analysed plasma TA concentrations of 8 patients undergoing elective cardiac surgery with CPB and high-dose TA (30 mg kg−1 bolus + 16 mg kg−1 h−1 infusion + 2 mg kg−1 priming dose). The authors found that actual plasma levels of TA were significantly higher than expected, based on previous modelling approaches [12, 13], and that 100% inhibition could be achieved at lower TA doses.

CLINICAL BOTTOM LINE Patients at high risk of bleeding should receive high-dose TA (30 mg kg−1 bolus + 16 mg kg−1 h−1 + 2 mg kg−1 priming), while those at low risk of bleeding should receive low-dose TA (10 mg kg−1 bolus + 1 mg kg−1 h−1 + 1 mg kg−1 priming) with consideration given to potential dose-related seizure risk. Conflict of interest: none declared.

REFERENCES [1] Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2:405–9. [2] Sigaut S, Tremey B, Ouattara A, Couturier R, Taberlet C, Grassin-Delyle S et al. Comparison of two doses of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Anesthesiology 2014;120: 590–600. [3] Waldow T, Szlapka M, Haferkorn M, Bürger L, Plötze K, Matschke K. Prospective clinical trial on dosage optimizing of tranexamic acid in nonemergency cardiac surgery procedures. Clin Hemorheol Microcirc 2013; 55:457–68. [4] Du Y, Xu J, Wang G, Shi J, Yang L, Shi S et al. Comparison of two tranexamic acid dose regimens in patients undergoing cardiac valve surgery. J Cardiothorac Vasc Anesth 2014;28:1233–7. [5] Armellin G, Vinciguerra A, Bonato R, Pittarello D, Giron GP. Tranexamic acid in primary CABG surgery: high vs low dose. Minerva Anestesiol 2004; 70:97–107. [6] Faraoni D, Cacheux C, Van Aelbrouck C, Ickx BE, Barvais L, Levy JH. Effect of two doses of tranexamic acid on fibrinolysis evaluated by thromboelastography during cardiac surgery: a randomised, controlled study. Eur J Anaesthesiol 2014;31:491–8. [7] Koster A, Börgermann J, Zittermann A, Lueth JU, Gillis-Januszewski T, Schirmer U. Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anaesth 2013;110:34–40. [8] Manji RA, Grocott HP, Leake J, Ariano RE, Manji JS, Menkis AH et al. Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors. Can J Anaesth J 2012;59:6–13. [9] Sharma V, Katznelson R, Jerath A, Garrido-Olivares L, Carroll J, Rao V et al. The association between tranexamic acid and convulsive seizures after cardiac surgery: a multivariate analysis in 11529 patients. Anaesthesia 2014;69:124–30. [10] Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg 2012;93:148–54. [11] Sharma V, Fan J, Jerath A, Pang KS, Bojko B, Pawliszyn J et al. Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass. Anaesthesia 2012;67:1242–50. [12] Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL et al. Pharmacokinetics of Tranexamic acid during cardiopulmonary bypass. Anesthesiology 2002;97:390–9. [13] Grassin-Delyle S, Tremey B, Abe E, Fischler M, Alvarez JC, Devillier P et al. Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Br J Anaesth 2013;111: 916–24.

What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is m...
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