Chornenki NLJ, Um KJ, Mendoza PA, et al. Risk of venous and arterial thrombosis in non-surgical patients receiving systemic tranexamic acid: A systematic review and meta-analysis. Thromb Res. 2019 Jul;179:81-86. doi: 10.1016/j.thromres.2019.05.003. Epub 2019 May 5. (Systematic review)

BACKGROUND: Antifibrinolytic agents such as tranexamic acid (TXA) are commonly used as adjunctive therapies to prevent and treat excessive bleeding. In non-surgical settings, TXA is known to reduce bleeding related mortality. However, impact of TXA use on thrombosis is uncertain.

METHODS: We systematically searched the MEDLINE, EMBASE, and CENTRAL databases from January 1985 to August 2018. Studies with the following characteristics were included: (i) RCT design; (ii) compared systemic (oral or intravenous) TXA for prevention or treatment of bleeding for non-surgical indications and placebo or no TXA, and (iii) reported thrombotic events or mortality. A Mantel-Haenzel, random-effects model was used to calculate risk ratios, and risk of bias was assessed using the Cochrane risk of bias tool.

RESULTS: Our search identified 22 studies representing 49,538 patients. Those receiving TXA had a significantly lower risk of death from any cause (RR?=?0.92; 95% CI?=?0.87-0.98; I2?=?0%). There was no significant increase in the risk of stroke (RR?=?1.10; 95% CI?=?0.68-1.78; I2?=?31%), myocardial infarction (RR?=?0.88; 95% CI?=?0.43-1.84; I2?=?46%), pulmonary embolism (RR?=?0.97; 95% CI?=?0.75-1.26; I2?=?0%), or deep vein thrombosis (RR?=?0.99; 95% CI?=?0.70-1.41; I2?=?0%) from use of TXA. The results were similar when restricted to studies at low risk of bias.

CONCLUSIONS: In our systematic review and meta-analysis, the use of tranexamic acid reduced all-cause mortality without increased risk of venous or arterial thrombotic complications.

Discipline Area Score
Hematology 7 / 7
Obstetrics 7 / 7
Hemostasis and Thrombosis 7 / 7
Gynecology 6 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Emergency Medicine 6 / 7
Gastroenterology 4 / 7
Comments from MORE raters

Emergency Medicine rater

Useful literature review and meta-analysis reinforcing the mortality benefit and lack of adverse events associated with systemic tranexamic acid, reinforcing continuously emerging evidence that TXA should likely be given early for any patient with significant acute bleeding.

Emergency Medicine rater

TXA is increasingly proposed as a cheap and readily available pharmacologic alternative for emergency medicine bleeding (epistaxis, post-partum vaginal, trauma, hemorrhagic stroke). Although TXA is a hemostatic agent that is only active on bleeding surfaces, the issue of safety is a recurring concern since other procoagulants increase the incidence of thrombotic complications. This meta-analysis again demonstrates no observed thrombotic events, which ought to improve clinicians' comfort using TXA in appropriate scenarios.

Emergency Medicine rater

This meta-analysis that included almost 50,000 patients found that tranexamic acid (TXA) decreases mortality (when used in the right patients) and does not increase clotting complications, including DVT/PE, stroke, or MI. Although not addressed directly in this meta-analysis, TXA appears to decrease mortality by decreasing bleeding and hemorrhage. As far as I can tell, it is the only drug that actually decreases hemorrhage in bleeding patients without evidence of increased clotting, which is quite remarkable. The authors urge caution when applying these results to patients with a history of thrombotic complications, as such patients were excluded from most of the primary studies.

Gastroenterology rater

Agent not used in USA.

Gynecology rater

While possibly clinically valuable information from this meta-analysis (of RCTs) was shown, it remains to be seen specifically what non-surgical patients would benefit from TXA prophylactic use. It is still unclear as to the clinical value of this information, at least for OB/GYN clinicians.

Gynecology rater

As a gynecologist, I am reassured by this article that systemic tranexamic acid can be used to stop bleeding without an increased risk for thrombosis.

Gynecology rater

This is important because of the boxed warning which providers in my discipline may equate to risks similar to hormonal contraceptives to control bleeding. It's reassuring to have this intermittent option that is likely underutilized.

Hematology rater

Well performed meta-analysis evaluating the risk for thrombosis in patients receiving antifibrinolytic therapy for non-surgical bleeding. There was no increase in thrombosis, but the optimal timing of administration is unknown and patients with prior thrombosis were excluded from the studies included in the meta-analysis. Overall, this should reassure the hematology community that antifibrinolytics are safe and provide clear benefit in patients with bleeding.

Hemostasis and Thrombosis rater

Despite precautions regarding thrombosis risk in the US labeling of TXA, studies have not convincingly shown such a risk exists. This well-executed meta-analysis provides further reassurance for the safety of TXA in regard to recurrent thrombosis.

Hemostasis and Thrombosis rater

This is an incredibly important publication and will hopefully do much to reverse the widespread misinformation that tranexamic acid increases the risk for thrombosis, even among hematologists who do not routinely use it in the management of bleeding disorders.

Internal Medicine rater

In this systematic review, the authors reviewed transexamic acid use to prevent bleeds in cancer, GI bleeds, and trauma cases. Not surprisingly, there was a very big variance in doses in the different studies. Although they included 22 different studies, 1 trauma study with 10,000 patients in each arm accounted for 50% to 70% of the weight of several of the outcomes. In the end, this intervention probably does not hurt trauma patients. Before it becomes a regularly used for others, studies of 1 particular dose in 1 particular disease are likely necessary.

Obstetrics rater

This meta-analysis included a large number of patients and provided clear conclusions: using tranexamic acid (TXA) does not increase risk for thrombosis. This is not surprising considering the pharmacology of TXA. The authors caution that this meta-analysis did not address the risk in patients who are at risk for thrombosis. Other individual studies, however, have reported using TXA in patients at risk for thrombosis that provide a reasonable safety record.

Obstetrics rater

Important topic - the safety information is probably the most relevant. Since pregnancy increases the risk for thrombotic events, it would have been nice to know whether there was no increase in those events in the 4 trials where TXA was used for postpartum hemorrhage.
Comments from EvidenceAlerts subscribers

Dr. Arvind Nana (7/1/2019 10:28 AM)

Interesting to see that one of the gastroenterology raters for this meta-analysis sayss that TXA is not used in the USA. That is incorrect. It is widely used in the USA, especially in orthopaedic surgery, which is my specialty. This rater should probably refine his comment to his field of gastroenterology.

Mr. Ayman Sofiyan (6/27/2019 10:01 AM)

There is considerable heterogeneity in the claims made about thromboembolic sequelae with wide confidence intervals. One should be cautious when interpreting the study conclusions around them.