What is the evidence regarding tranexamic acid use in angioedema? What dose should be used?

Comment by InpharmD Researcher

According to societal guidelines, tranexamic acid (TA) is not recommended for acute treatment of hereditary angioedema due to minimal benefit, but it may be considered for long-term prophylaxis when first-line options are unavailable or contraindicated. In idiopathic and bradykinin-mediated angioedema, including angiotensin-converting enzyme inhibitor (ACE-i)-induced cases, limited evidence suggests that TA may reduce the frequency, duration, and severity of episodes, though responses vary. Doses used for acute treatment have ranged from 1 to 2 grams every four hours up to 3 grams total in 24 hours. Although data remain limited and largely observational, TA appears to have a favourable safety profile and may be a reasonable option in select cases where other therapies are inaccessible.

Background

A 2004 case series reported on seven patients with chronic, non-histaminergic angioedema who were unresponsive to antihistamines and corticosteroids. All patients were treated with tranexamic acid at a dosage of 1 gram three times daily. This regimen led to complete remission of symptoms in three patients and a marked reduction in frequency and intensity of episodes in the remaining four. The diagnosis in these cases was idiopathic non-histaminergic (bradykinin-mediated) angioedema, supported by normal C1 inhibitor levels and function in six patients, with one showing transient dysfunction linked to estrogen use. For acute attacks, administration of 1 to 2 grams of tranexamic acid every four hours over 24 hours was associated with a reduction in edema duration and severity. No adverse effects were reported during an average follow-up of 20 months. Notably, these findings suggest that tranexamic acid may be both a diagnostic aid and a therapeutic option for non-histaminergic angioedema. [1]

A 2009 retrospective observational analysis evaluated the clinical characteristics, diagnostic timeline, and response to TA in 35 patients diagnosed with sporadic idiopathic bradykinin-mediated angioedema (BAO). This non-hereditary, non-drug-induced form of BAO was characterized by the absence of urticaria and resistance to conventional therapy with H1-antihistamines, corticosteroids, and epinephrine. Episodes varied in frequency from daily to less than once per year and lasted a mean of 36.3 hours, with presentations involving various anatomical sites; however, head and neck involvement was universal. Despite some hospitalizations, no invasive interventions were required. Out of the 35 patients, 25 received on-demand TA at a dosage of 1 gram during acute episodes. TA demonstrated clinical efficacy in 23 of these cases, evidenced by significant reductions in episode intensity and duration, which led to the initiation of daily maintenance therapy at 3 grams. Twelve patients achieved complete remission, with six eventually able to reduce the dose. Eleven patients experienced substantial decreases in episode frequency and severity. TA was generally well tolerated over a mean follow-up of 20 months, showing a more favorable safety profile compared to danazol, with only two patients discontinuing due to ineffectiveness or gastrointestinal intolerance. Ten individuals did not receive TA due to various reasons, including thromboembolic risk, alternative therapies, or infrequent symptomatology. Based on these findings, TA offers a viable diagnostic and therapeutic approach in cases of idiopathic, bradykinin-mediated angioedema unresponsive to standard treatment, supporting its use as a first-line option in the absence of contraindications. [2]

A 2024 retrospective study evaluated the use of tranexamic acid in patients with angiotensin-converting enzyme inhibitor-induced angioedema (ACE-IIA) across 17 emergency departments. The study included 262 adult patients, with 73 receiving tranexamic acid and 189 serving as controls. The primary outcome was emergency department (ED) length of stay (LOS), with secondary outcomes including ICU admissions, intubations, and safety events. Patients treated with tranexamic acid had a significantly longer median ED LOS (40.3 vs. 21.1 hours, p <0.0001), higher rates of ICU admission (45.2% vs. 15.9%, p <0.0001), and increased intubation rates (12.3% vs. 6.4%, p = 0.11). No differences were observed in 7-day return visits, thrombotic events, or mortality. The most common initial dose of tranexamic acid was 1000 mg IV, with a range of 1000–2000 mg; total doses ranged from 1000–3000 mg. Overall, the study concluded that while tranexamic acid appears safe, its administration was associated with more severe presentations and did not reduce LOS. Prospective randomized controlled trials are recommended to determine its efficacy in ACE-IIA. [3]

The international 2021 updated guidelines published by the World Allergy Organization (WAO) and European Academy of Allergy and Clinical Immunology (EAACI) recommend the use of icatibant or ecallantide for on-demand treatment of hereditary angioedema (HAE) attacks as early as possible. In contrast, fibrinolytic agents like tranexamic acid (TA) are not recommended for the acute management of angioedema due to reporting no or minimal benefit. While icatibant and ecallantide are not used for long-term prophylaxis, they may be retained for use during acute episodes. TA for long-term prophylaxis (LTP) is only recommended if first-line prophylactic agents are unavailable and androgens are contraindicated (e.g., pediatric patients). While data is lacking for TA prophylaxis, the safety profile is deemed acceptable for the agent's recommendation. For long-term prophylaxis, the doses of TA used range from 30 to 50 mg/kg body weight daily divided into two or three doses to a maximum of 6 g per day. [4]

Per the United States Hereditary Angioedema Association Medical Advisory Board (US HAEA MAB) 2020 Guidelines for the Management of Hereditary Angioedema, antifibrinolytic medications (e.g., TA or epsilon aminocaproic acid) have been successfully used for LTP in HAE-C1INH but are less effective than recommended first-line therapies (e.g., intravenous [IV] pdC1INH replacement, subcutaneous [SC] pdC1INH replacement, monoclonal inhibitor of plasma kallikrein), thus seldom used for LTP of HAE due to a deficiency of C1INH (HAE-C1INH) in the US. TA (Lysteda) is available with the usual dose starting at 650 mg PO BID, increasing to 1300 mg PO BID bid if required. Creatinine should be monitored for any impairment requiring dose adjustment. Potential related side effects include thrombosis, gastrointestinal upset, myalgia, and dysmenorrhea. [5]

A 2023 review article discusses the role of tranexamic acid for angiotensin-converting enzyme inhibitor-induced angioedema (ACE-IA). The mechanism of action for tranexamic acid in treating ACE-IA is not thoroughly understood. However, tranexamic acid’s inhibition of plasmin activation is integral to its antifibrinolytic effect, crucial in enhancing kallikrein (a precursor of bradykinin) activation. Tranexamic acid hinders the generation of inflammatory peptides induced by fibrin and reduces the transformation of kininogen into bradykinin. C1 esterase activates plasma kallikrein and factor XIIa, facilitating downstream bradykinin development. Further research is necessary to elucidate the precise mechanisms through which tranexamic acid exerts its therapeutic effects in this patient population. [6]

A 2018 systematic review evaluated the efficacy of icatibant, ecallantide, and TA for angiotensin-converting enzyme inhibitor (ACEi) induced and idiopathic AE (non-hereditary AE). This systematic review included 61 studies, with 38 describing treatment in the acute setting, although most of the evidence was from case reports. There were no direct comparisons between icatibant, ecallantide, or TA. For idiopathic AE, a single study on TA use observed a 54% response rate (13 to 24 patients). Data for icatibant and ecallantide are limited to response times. Icatibant reported an initial response time of 20 to 45 minutes. For complete response, icatibant reported a range between 45 minutes to 26.6 hours, while ecallantide complete response was <1 hour. However, only one case report was available for ecallantide, while icatibant presented various case reports and two cohorts. Prophylactic treatment of idiopathic AE using TA found improvement of symptoms in 73% of patients, based on six studies, and 16% achieved complete absence of symptoms. Prophylaxis with icatibant and ecallantide was unexplored. Based on these results, the authors prefer icatibant over ecallantide for ACEi-induced or idiopathic AE, while TA may have been used as a prophylaxis agent against idiopathic AE. However, with the lack of direct comparative data, the optimal agent of the three remains uncertain. [7]

Overall, data regarding the use of TA in managing ACEi-AE are severely limited. Aside from a non-comparative retrospective study (see Table 1), a case report, and an untranslated French study have described the successful use of TA in treating patients with ACEi-AE. The French study was unique in that TA was the sole therapeutic option for severe ACEi-AE. Twenty-seven of 33 patients observed significant improvement, while the other 6 patients were treated with icatibant or C1INH concentrates. The authors of the French study concluded that TA may serve as an effective treatment or help while awaiting more specific treatment such as icatibant. [8], [9]

References:

[1] Bouillet L, Ponard D, Drouet C, Massot C. Intérêt diagnostic et thérapeutique de l'acide tranexamique dans les angio-oedèmes non-histaminiques [Non-histaminic angiodema management: diagnostic and therapeutic interest of tranexamic acid]. Rev Med Interne. 2004;25(12):924-926. doi:10.1016/j.revmed.2004.07.018
[2] Du-Thanh A, Raison-Peyron N, Drouet C, Guillot B. Efficacy of tranexamic acid in sporadic idiopathic bradykinin angioedema. Allergy. 2010;65(6):793-795. doi:10.1111/j.1398-9995.2009.02234.x
[3] Lindauer KE, Lo BM, Weingart GS, et al. Tranexamic acid for angiotensin converting enzyme inhibitor induced angioedema: A retrospective multicenter study. Am J Emerg Med. 2024;79:33-37. doi:10.1016/j.ajem.2024.02.006
[4] Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022;77(7):1961-1990. doi:10.1111/all.15214
[5] Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-150.e3. doi:10.1016/j.jaip.2020.08.046
[6] Pathak GN, Truong TM, Chakraborty A, Rao B, Monteleone C. Tranexamic acid for ace inhibitor-induced angioedema. Clin Exp Emerg Med. Published online August 1, 2023. doi:10.15441/ceem.23.051
[7] van den Elzen M, Go MFCL, Knulst AC, Blankestijn MA, van Os-Medendorp H, Otten HG. Efficacy of Treatment of Non-hereditary Angioedema. Clin Rev Allergy Immunol. 2018;54(3):412-431. doi:10.1007/s12016-016-8585-0
[8] Wang K, Geiger H, McMahon A. Tranexamic acid for ACE inhibitor induced angioedema. Am J Emerg Med. 2021;43:292.e5-292.e7. doi:10.1016/j.ajem.2020.10.029
[9] Beauchêne C, Martins-Héricher J, Denis D, Martin L, Maillard H. Intérêt de l’acide tranexamique en traitement d’urgence de première intention des crises d’angiœdème bradykinique sous IEC [Tranexamic acid as first-line emergency treatment for episodes of bradykinin-mediated angioedema induced by ACE inhibitors]. Rev Med Interne. 2018;39(10):772-776. doi:10.1016/j.revmed.2018.04.014

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence regarding tranexamic acid use in angioedema? What dose should be used?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→



Please see Tables 1-2 for your response.


 

Tranexamic Acid for the Emergency Treatment of Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema

Design

Retrospective cohort study

N= 16

Objective

The purpose of this study is to evaluate the impact of tranexamic acid administration on rates of intubation in patients presenting to the emergency department (ED) with suspected angiotensin-converting enzyme (ACE) inhibitor-induced angioedema (ACEi-AE)

Study Groups

Patient data (N= 16)

Inclusion Criteria

Patients who received TXA for ACEi-AE in the ED, age > 18 years, recent ACE inhibitor use per physician documentation or outpatient fill history (within the last 90 days)

Exclusion Criteria

Signs and symptoms consistent with histamine-mediated angioedema or anaphylaxis; family history of hereditary or acquired angioedema; administration of icatibant, ecallantide, or a C1-INH product prior to receiving TXA; admission to the trauma service

Methods

Patient data was screened in a reverse chronological fashion for those who fulfill the inclusion criteria. The data consisted of patients from a single-center ED with more than 210,000 visits per year. No protocol existed for the treatment of ACEi-AE; the use of TXA was at the discretion of the physician. Other agents such as ecallantide, icatibant, and C1-INH concentrates were not available on the hospital formulary.

Fifteen of 16 patients received TXA 1,000 mg IV over 10 minutes. One patient received TXA 100 mg IV.

Duration

Data collection period: January 1, 2019 to March 31, 2021 

Outcome Measures

Primary: Proportion of patients who required intubation for suspected ACEi-AE following TXA administration

Secondary: Rate of hospital admission from the ED, time of resolution of symptoms, incidence of adverse events, ED length of stay

Baseline Characteristics

 

Patient data (n= 16)

Age, years

64.3

Male

10 (62.5%)

White

9 (56%) 

Past medical history

Venous thromboembolism

Congestive heart failure

 

0

1 (6%)

Outpatient ACEi therapy

Lisinopril

Lisinopril/hydrochlorothiazide

Amlodipine/benazepril

 

12 (75%)

1 (6%)

3 (19%)

Median duration of ACE inhibitor use, months (interquartile range [IQR])

22.5 (9 to 54.5)

Clinical presentation

Erythema

Dyspnea

Peripheral swelling

Facial swelling

Tongue

Lips

0

4 (25%)

0

0

16 (100%)

11 (69%)

5 (31%)

Treatment administered

TXA

Diphenhydramine

Famotidine

Methylprednisolone

Nebulized racemic epinephrine

IM epinephrine

SC epinephrine

Fresh frozen plasma

 

16 (100%)

13 (81%)

10 (63%)

12 (75%)

3 (19%)

1 (6%)

1 (6%)

4 (25%)

Results

Endpoint

Patient data (n= 16)

Required intubation after TXA administration*

0

Time from TXA administration to resolution, minutes (standard deviation [SD])

Repeat TXA administration required

100 (26)

1 (6%)

Required transfer to the intensive care unit (ICU)

ICU length of stay, days (IQR)

3 (18%)

1.9 (1.5 to 6.2)

Discharged alive

16 (100%)

ED visit for a recurrent attack within 90 days

1 (6%)

*Two of the 16 patients required intubation prior to the administration of TXA.

Adverse Events

TXA adverse effects were not observed including hypotension, anaphylaxis/hypersensitivity reaction, thrombosis within 28 days, transfusion-associated circulatory overload, transfusion-related acute lung injury, or worsening angioedema

Study Author Conclusions

Administration of TXA was associated with a low rate of adverse effects and did not contribute to further morbidity when added to standard care in patients presenting to the ED with suspected ACEi-AE.

InpharmD Researcher Critique

This was a non-comparative study. Retrospective studies remain limited by the accuracy of their data within the electronic health records. Furthermore, the data was collected from a single site which reduces the generalizability to other locations with different protocols. Data for patients was limited to 90 days. Other treatments were typically administered in conjunction with TXA which makes it difficult how contributory TXA's effect was.



References:

Hasara S, Wilson K, Amatea J, Anderson J. Tranexamic Acid for the Emergency Treatment of Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema. Cureus. 2021;13(9):e18116. Published 2021 Sep 20. doi:10.7759/cureus.18116

 

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

Design

Double-blind, randomized, multicenter trial (FAST-2)

N= 74

Objective

To report the results of a phase 3 study (FAST-2) comparing icatibant was compared with tranexamic acid for hereditary angioedema (HAE)

Study Groups

Icatibant (n= 36)

Tranexamic acid (n= 38)

Inclusion Criteria

Age 18 years or older, documented diagnosis of hereditary angioedema type 1 (antigenic deficiency of C1 esterase inhibitor) or type 2 (functional deficiency of CI esterase inhibitor)

Exclusion Criteria

Diagnosis of angioedema other than hereditary angioedema, serious concomitant illness, pregnancy/lactation

Methods

Patients in the FAST-2 trial were randomized (1:1) to receive either icatibant 30 mg subQ or tranexamic acid 3 g PO daily for 2 days. Blinding was maintained via a double-dummy design. Two further doses of oral medication (either tranexamic acid or placebo) were given on day 1, at 6-hour and 12-hour apart of the initial study drug administration, followed by three further doses, each 6-8 hours apart, on day 2. Any patients that developed a subsequent attack were enrolled into an open-label extension phase to receive icatibant, including life-threatening angioedema.

Duration

24 weeks

Outcome Measures

Primary: median time to clinically significant relief of the index symptom (minimum decrease of visual analog scale of 20-30 mm, depending on initial symptom severity) and sustained for 3 consecutive measurements.

Secondary: median time to first symptom improvement, time to almost complete relief symptoms, clinically significant relief of the index symptom at 4 hours

Baseline Characteristics

 

Icatibant (n= 36)

Tranexamic acid (n= 38)

 

Age, years

40.4 ± 13.6 41.9 ± 12.4  

Female

24 (67%) 23 (61%)  

Type of HAE

Cutaneous

Abdominal

 

24

12

 

23

15

 

No. of attacks in the previous 6 months, median (range)

Cutaneous

Abdominal

Both

Laryngeal

 

6 (1–24)

3 (1–15)

4 (1–24)

2 (1–7)

 

5 (1–7)

3 (1–72)

2 (1–12)

1 (1–6)

 

Results

Endpoint

Icatibant (n= 36)

Tranexamic acid (n= 38)

p-Value

Time to clinically significant relief of index symptom, hours (interquartile range [IQR])

2.0 (1.0 to 3.5)

12.0 (3.5 to 25.4)

< 0.001

Time to first symptom improvement, hour (IQR)

According to patient

According to investigator

 

0.8 (0.4 to 1.4)

1.5 (0.7 to 3.0)

 

7.9 (1.1 to N/A)

6.9 (4.0 to 13.8)

< 0.001

Time to almost complete relief of symptoms, hours (IQR)

 

10.0 (2.8 to 23.2) 51.0 (12.0 to 79.5) < 0.001

Clinically significant relief of the index symptom at 4 hours

80 (63 to 92) 31 (16 to 48) < 0.001

Adverse Events

Drug-related adverse events occurred in 5 (14%) of the icatibant group versus 4 (11%) of the tranexamic acid group.

Events in the icatibant group included abdominal pain, nausea, and worsening of acute angioedema episode

Serious adverse events were more frequent with icatibant (11% vs 3%) but were considered unrelated to the study drug treatment.

Study Author Conclusions

In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary endpoint. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial.

InpharmD Researcher Critique

Due to the rarity of the disease, it is understandably difficult to enroll a higher patient population. However, the primary outcome of a reduction in index symptoms by 20-30 mm may not be sufficient to warrant clinical significance, although the secondary outcomes included the patient's assessment which greatly favored icatibant.



References:

Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema [published correction appears in N Engl J Med. 2010 Oct 7;363(15):1486]. N Engl J Med. 2010;363(6):532-541. doi:10.1056/NEJMoa0906393