The 2022 International Consensus Group (ICM)-venous thromboembolism (VTE) guidelines provided general recommendations on the risk associated with using tranexamic acid (TXA) and the development of VTE. The panel stated that the administration of TXA in patients undergoing orthopedic procedures does not increase the risk of developing subsequent VTE in patients without prior VTE history (strong recommendation). Even though most patients with prior VTE were excluded in published studies, moderate quality data exists to support TXA use in high-risk orthopedic procedures with prior VTE or other hypercoagulable conditions (e.g., stroke, cancer, atrial fibrillation). A 2017 retrospective matched cohort study of more than 1,200 patients with prior VTE found the risk of recurrent VTE was not significantly greater in patients who received perioperative VTX administration; of the 31 patients who experienced recurrent VTE, TXA administration was not independently associated with increased risk. Another retrospective study of 38,220 total joint arthroplasty patients with prothrombotic conditions also found TXA was not associated with an increase in adverse outcomes in high-risk patients. The decision to utilize TXA must not be solely based on the theoretical risk of VTE, but instead must weigh all risks and benefits to the medication. It is important to note that patients with higher comorbidity burden (e.g., prior VTE, CAD, ASA score ≥ 3, malignancy) are known to have a higher risk of complication following significant blood loss and blood product transfusion and, as such, indirectly benefit from routine TXA usage where there is lack of evidence to suggest harm from TXA administration. [1], [2], [3]
A 2021 retrospective cohort comparison using national claims data (Premier Healthcare) of 71,174 who underwent a total or reverse shoulder arthroplasty identified 9,735 (13.7%) patients in whom the TXA was used during the procedure (34.8% TXA 1,000 mg; 45.8% 2,000 mg TXA). Among TXA users, 1,033 (10.6%) of patients had a history of thrombotic events such as myocardial infarction, DVT, pulmonary embolism, transient ischemic attack, or ischemic stroke (61,439 non-TXA users; 10.5% history of thrombotic events). After adjustment for relevant covariates, overall, TXA use was not associated with increased odds of complications, irrespective of preoperative patient comorbidity burden/risk status. In a subgroup of TXA patients with a history of thrombotic events, TXA use was associated with a slight reduction in hospitalization cost (8.9% CI: 13.1%; 4.6%; p<0.0001; group median $18,830) compared with no TXA use. Based on these findings, the authors concluded among shoulder arthroplasty patients, TXA use was not associated with increased complication odds, independent of a history of thrombotic events. [4]
A 2021 retrospective study investigated the impact of the previous stroke on the risk of TXA-associated seizures. Data were compiled from records of 16,110 patients who had undergone open-heart valvular surgery at a single institution; patients had been given TXA with a bolus of 1 g after heparinization, followed by an infusion of 0.2 g/h until the end of cardiopulmonary bypass. Compared to patients without TXA administration, the adjusted odds ratio (OR) of experiencing a seizure in TXA patients without a history of stroke was 2.44 (95% CI 1.71 to 3.46), whereas in patients receiving TXA with a history of stroke 4.30 (95% CI 2.65 to 6.99). There was no significant interaction between TXA use and preoperative stroke for convulsive seizures. [5]
A 2021 systematic review and meta-analysis examined the association between intravenous TXA with thromboembolic events and mortality. A total of 176 of 219 randomized controlled trials (n= 101 orthopedic studies; n= 6 maxillofacial studies) provided thromboembolic events data (N= 65,900; TXA groups, n= 33,487; Control, n= 32,413). While the incidence of thromboembolic events was higher in the TXA group compared to the control group (2.3% vs. 2.2%), the overall TXA utilization was not significantly associated with an increased risk of thromboembolic events (p= 0.66). Increased risk for vascular occlusive events was not found in studies including patients with a history of thromboembolism. [6]
Additionally, extensive data was available focusing on risk of thrombotic events associated with TXA in general, without focusing specifically on patients with a history of thrombotic events. A 2021 meta-analysis of 234 randomized controlled studies (N= 102,681; 124 in orthopedic surgery) of patients treated with TXA versus no intervention (placebo) found no overall evidence of TXA increasing the risk of thrombotic events (risk ratio [RR] 1.00; 95% CI 0.93 to 1.08; I2= 0%). The risk of VTE, acute coronary syndrome, or stroke was also similar between groups. However, seizures were significantly greater in patients who received more than 2 g/day of TXA (RR 3.05; 95% CI 1.01 to 9.20; p= 0.011). Subgroup analyses based on different types of procedures also did not observe any increase in thrombotic events in trauma (RR 0.89; 95% CI 0.69 to 1.17), obstetrics and gynecology (RR 0.81; 95% CI 0.53 to 1.26), cardiac surgery (RR 0.92; 95% CI 0.81 to 1.05), orthopedic surgery (RR 0.98; 95% CI 0.80 to 1.21). While TXA did not appear to increase the risk of thrombotic events, caution is advised against using higher doses due to the possible increased risk of seizures. [7]
A 2022 meta-analysis investigated the safety and effectiveness of topical TXA in spinal surgery (8 randomized controlled trials, 884 patients). The incidence of VTE was observed in 3.1% (7/226) of the patients in the TXA group and 1.7% (4/229) of patients in the control group (treated with no TXA or isotonic saline). There was no significant difference in the incidence of deep vein thrombosis between the two groups (OR 1.48; 95% CI 0.41 to 5.34, p= 0.55). Based on these findings, the authors suggested that TXA could be safely used during the perioperative period and does not increase the risk of VTE in patients. [8]
Additionally, a 2022 meta-analysis examined the association of TXA administration with mortality and thromboembolic events compared with no treatment or with placebo in patients (aged ≥ 15 years) with traumatic injuries. A total of 31 studies (6 randomized controlled trials and 25 observational studies; N= 43,473) were included for analysis. Due to the significant heterogeneity in regards to 24-hour mortality, a quantitative analysis was not conducted for this outcome. Pooled data for 1-month mortality revealed a significantly decreased mortality in the TXA group compared to the control group (RR 0.83; 95% CI 0.71 to 0.97). Again, substantial heterogeneity was noticed for reported thromboembolic events; estimates of RRs varied from 0.14 (95% CI 0.01 to 2.69) to 24.12 (95% CI 1.42 to 408.88). Thus the risk of VTE remained inconclusive, as 12 studies revealed higher and 8 studies showed lower incidences of thromboembolic events for tranexamic acid treatment compared with the control cohort. [9]
Although TXA has been widely used as a hemostatic adjunct for hemorrhage control in the injured patient, the risk of VTE associated with its use in trauma patients has not been fully evaluated. A 2019 propensity-matched analysis assessed the association between TXA and VTE following trauma in 189 paired patients, with a median Injury Severity Score of 19 and 14 (interquartile range 8-22) in the TXA and non-TXA groups, respectively. The primary outcome of incidence of VTE occurred in 15.3% of patients receiving TXA compared to 7.4% of non-users. Among all VTE events, DVT represented 51.7% and 50.0% of cases in the treated and untreated groups, respectively. The adjusted analysis found TXA to be associated with a significantly higher risk of VTE (adjusted OR [aOR] 3.3; 95% CI 1.3 to 9.1; p= 0.02). The risk of VTE remained elevated in the TXA cohort despite accounting for mortality (subdistribution hazard ratio, 2.42; 95% CI 1.11 to 5.29; p= 0.03). Because the study revealed TXA as an independent risk factor for VTE, the authors suggest carefully selecting injured patients for TXA use is necessary. [10]