The Local Use of Tranexamic Acid Is it a Myth??

1. The Local Use of Tranexamic Acid Is it a Myth?? Dr. Dina Salah El Din Mahmoud Ass. Prof. of Anesthesia, ICU and Pain management. Ain Shams University Dr. Yasmin Mahmoud Aboul-Ela Lecturer of Clinical Pharmacology, Ain Shams University

2. Case Report • A 71-year-old female, admitted to the ICU with an attack of hematemesis and melena. • She has a history of being diabetic and hypertensive. She is dementic, bed ridden due to a previous attack of stroke.

3. On Examination • She had chest infection, bed sores in the buttocks. • Bilateral lower limb edema, for which lower limb duplex was done that showed bilateral DVT extending to iliac veins.

4. Dilemma to manage • DVT that needs Anticoagulation in a patient that has Hematemesis & Melena • !!!!!!

5. Preliminary Management • Initial resuscitation was done with fluids and blood as needed. • In order to stop hematemesis, local tranexamic acid (TXA) was used in the administered gastric wash, for this patient, till bleeding decreased enough to perform emergency upper GI endoscopy. • This patient was further scheduled for application of IVC filter on a later date.

6. So…. • Is using Tranexamic acid locally offers a therapeutic benefit from • the pharmacological point of view?? • Does it work locally or exert its action through systemic absorption? • Can it be used locally to stop heavy bleeding ?? • What about the adverse effects??

7. How TXA works? • TXA was introduced for menorrhagia in 1968 and is used to reduce blood loss during surgery. • This drug reduces fibrinolysis by slowing down the conversion of plasminogen to plasmin. The resulting reduction in fibrinolysis prevents the breakdown of blood clots, which may result in hemostasis.

8. Intravenous tranexamic acid reduces bleeding in surgery, however, its effect on the risk of thromboembolic events is uncertain and an increased risk remains a theoretical concern. • Due to a probable less systemic absorption following topical administration, the direct application of tranexamic acid to the bleeding surface has the potential to reduce bleeding with minimal systemic effects.

9. What is the state of current Evidence that supports the Local Use of TXA?

10. Does it work locally or exert its action through systemic absorption? • The presumed concerns about thromboembolic events have stimulated increasing interest in the topical use of tranexamic acid. • Studies (dental surgeries, hip arthroplasty & ulcerative colitis) suggest that plasma concentrations following the topical application of tranexamic acid are less than one tenth of the level after oral or intravenous administration. • Plasma concentrations after topical TXA didn’t reach therapeutic levels that were considered liable to impair systemic fibrinolysis.

11. In 2013, a review was published about the • “Topical application of TXA for the reduction of bleeding” • in the Cochrane Database of Systematic Reviews. • 29 trials were included in this review, among which, 28 trials investigated the effect of local TXA (0.7-100mg/ml saline solution) in surgical bleeding and only 1 trial for control of bleeding in epistaxis. • Among the 28 surgical bleeding trials, 13 were for intra-articular TXA in hip/knee arthroplasty, 6 in heart surgeries, 4 in dental surgeries, 2 in endoscopic sinus surgeries, besides post adenoidectomy, thoracic surgery & post TURP hematuria.

12. It was concluded that… • There is reliable evidence that topical application of TXA reduces bleeding (by 29%-43%) & blood transfusion (by 45%-33%) in surgical patients, however the effect on the risk of thromboembolic events is uncertain, due to lack of reports in some trials. • The effects of topical TXA in patients with bleeding from non-surgical causes has yet to be reliably assessed. • Further high-quality trials are warranted to resolve these uncertainties before topical TXA can be recommended for routine use.

13. Risk vs Benefit

14. TXA in non-surgical patients?? • The CRASH-2 (Clinical Randomization of Antifibrinolytic in Significant Hemorrhage) trial, was a randomized, multi-center, placebo-controlled trial of the effect of TXA (IV) on death and vascular occlusive events in adult trauma patients (20,211) with, or at risk of, significant bleeding. • The trial has shown that administration of TXA to bleeding trauma patients who are within 3 hours of injury, reduces death due to bleeding and all cause mortality without increasing the risk of vascular occlusive events.

15. Problem: in almost all trials either using local or systemic TXA, patients with existing or history of thromboembolic events were excluded form the trials. • That’s why the results of the ATACAS trial, published in 2017 were crucial, as specifically patients at increased risk of thromboembolic events were enrolled. • The ATACAS results (Aspirin-TXA coronary artery surgery): Among patients undergoing coronary-artery surgery, TXA (2311 patients) was associated with a lower risk of bleeding than was placebo, without a higher risk of death or thrombotic complications within 30 days after surgery, albeit TXA was associated with a higher risk of postoperative seizures (dose related).

16. What about the use of TXA in Upper GI Bleeding???

17. Gastrointestinal bleeding related to portal hypertension is a serious complication in patients with liver cirrhosis. Most patients bleed from esophageal or gastric varices. • The control of gastrointestinal bleeding is more difficult to achieve in liver cirrhosis patients than in patients with normal hepatic function due to impaired hemostasis. • A previous published study (Bondok et al.) showed that addition of TXA to nasogastric lavage in patients with hematemesis significantly improved hemodynamic stability, decreased time of bleeding, transfusion requirements, and time taken to perform upper endoscopy. • The study also revealed no incidence of complications from using local TXA (stroke, myocardial infarction, deep vein thrombosis, pulmonary embolism) or death.

18. In 2014, the Cochrane Database of systematic reviews published a review “Tranexamic acid for upper gastrointestinal bleeding”. • The review aimed to assess the effects of TXA (IV/oral) versus no intervention, placebo or other antiulcer drugs for upper gastrointestinal bleeding. • 8 RCTs on TXA for upper GI bleeding were included, causes varied between bleeding from peptic, duodenal ulcer or esophageal varices. • These trials found that TXA appears to have a beneficial effect on mortality, but due to a high dropout rate in some trials, recommendations cannot be made until additional research is published .

19. The need for evidence is mandatory • to highlight the plausibility of using topical TXA in • upper GI bleeding • A well-planned large randomized controlled trial • With appropriate concealment • Well defined outcomes; including amount of blood loss, need for blood transfusion, thrombotic adverse events and seizures • Comparing plasma levels of oral/IV TXA vs Topical TXA