Effect of tranexamic acid in the treatment of angiotensin‑converting enzyme inhibitor‑induced angioedema: A systematic review and meta‑analysis

Abstract

OBJECTIVE: To assess the effectiveness of tranexamic acid (TXA) in the treatment of angiotensin converting enzyme inhibitor induced angioedema.

METHODS: A systematic review was conducted using PubMed, Scopus, Embase, and ProQuest databases from inception to January 2025, following PROSPERO registration (CRD42025524300). We included observational studies that evaluated the use of TXA in angiotensin converting enzyme inhibitor induced angioedema. Proportion meta analyses were performed on the data obtained from the selected studies.

RESULTS: Only four retrospective studies met the inclusion criteria, including two cohort studies, one retrospective study, and one case series, encompassing a limited sample size of 133 patients. Meta analysis showed that approximately 98% of patients treated with TXA did not require intubation, and 76% avoided intensive care unit admission. However, the absence of randomized controlled trials and the retrospective nature of the studies substantially limit the strength and generalizability of these results.

CONCLUSION: TXA may be a potential treatment option for angiotensin converting enzyme inhibitor induced angioedema by lowering intensive care unit admission and intubation; however, current evidence is limited and primarily retrospective. Robust prospective, randomized controlled trials are needed to draw definitive conclusions.

Introduction

Angiotensin converting enzyme inhibitors (ACEIs) are commonly used for hypertension, heart failure, and chronic kidney disease, but a major side effect is angioedema. Unlike histamine mediated angioedema, ACEI induced angioedema is mediated by bradykinin, which does not respond to corticosteroids, antihistamines, or epinephrine.[1,2] Angiotensin converting enzyme (ACE) inhibition leads to bradykinin accumulation, which results in swelling, most often involving the lips, face, tongue, pharynx, and larynx. Airway involvement can lead to life threatening obstruction, sometimes requiring intubation or intensive care unit (ICU) care.[1 3] Despite ACEIs being widely prescribed, there are no Food and Drug Administration approved treatments for ACEi angioedema. Management typically involves discontinuing the ACEI and airway support, while conventional therapies provide limited benefit. For severe cases, options such as tranexamic acid (TXA), icatibant, and ecallantide have been explored. TXA, an anti fibrinolytic agent, may reduce bradykinin production, but evidence is limited to retrospective studies. This review aims to assess TXA’s effectiveness and safety for ACEI induced angioedema. By synthesizing existing data, this review aims to provide clinicians with a clearer understanding of TXA’s role in managing this challenging condition and to highlight the need for further high quality research.

Material and Methods

Study design

This systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO ID CRD42025524300) and conducted following Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines to ensure methodological rigor and transparency.[4]

Eligibility criteria

Studies were selected for inclusion based on the following predefined criteria:

Participants

Studies involving patients of any age, sex, or clinical setting diagnosed clinically with angioedema attributed to ACEI use.

Intervention

Studies that used TXA, regardless of dose, route (intravenous or oral), frequency, or formulation, as part of the therapeutic approach for ACE inhibitor-induced angioedema.

Comparator

Studies that compared TXA to standard care (e.g.,supportive management, corticosteroids, antihistamines, epinephrine, or fresh frozen plasma [FFP]), placebo, or those with no comparator or control arm were considered eligible.

Outcomes

Studies that reported on the need for intubation, ICU admission, length of hospital stay, symptom resolution time, adverse events, or mortality following TXA administration.

Study design

Randomized controlled trials (RCTs) and any form of observational studies (prospective, retrospective, case control studies, cohort studies, and case series) were included.

Search strategy

We conducted extensive searches across multiple databases (PubMed, EMBASE, Scopus, and ProQuest). Two independent reviewers (KIC and SP) utilized a variety of search terms, such as (“tranexamic acid,” “antifibrinolytic agent”), (“angiotensin converting enzyme inhibitor,” “ACE inhibitor,” “enalapril,” “captopril”), and (“angioedema”), applying different field codes (e.g., “TITLE ABS KEY,” “ti ab kw,” “noft”) and Boolean operators (AND, OR, NOT). No restrictions were imposed based on publication date, country, or language. In addition, we reviewed the references of the selected articles for further relevant studies. Gray literature, preprints, or conference abstracts were not included. The initial database search was conducted on January 25, 2025 and reconfirmed on February 28, 2025.

Study selection

To enhance methodological rigor, a two stage screening process was employed for study selection, where two reviewers (KIC and SP) independently screened titles, abstracts, and full texts for eligibility.[5] Interrater agreement was assessed using Cohen’s kappa, which yielded a value of 0.80, indicating good agreement between reviewers and supporting the reliability of the selection process. Discrepancies between reviewers were finally resolved by a third reviewer (SM).

Data extraction and management

Two reviewers (KIC and SP) independently extracted data on study characteristics, baseline details, and outcomes in ACEI induced angioedema patients treated with TXA, focusing on the proportion of patients not requiring intubation or ICU admission. A third reviewer (SM) verified data accuracy.

Risk of bias assessment of the studies

The methodological quality and risk of bias of all included studies were assessed by two reviewers (KIC and SM) using validated tools as per Cochrane guidelines. The Risk Of Bias In Non randomized Studies of Interventions (ROBINS I) tool was used for nonrandomized studies, evaluating seven key bias domains. Each domain was rated as low, moderate, serious, or critical risk of bias, and an overall judgment was assigned accordingly. The Joanna Briggs Institute (JBI) checklist was used for case series. Disagreements were resolved by discussion and consultation with a third reviewer (SP).

Statistical analysis

Analyses were performed using Stata MP version 17. The Freeman–Tukey double arcsine transformation was used to stabilize variance in proportions, particularly for studies with skewed/extreme values (near 0 or 1), which can otherwise lead to biased/imprecise pooled estimates. This method reduces the influence of such studies and improves the distribution’s normality, enhancing the robustness of the analysis, especially in the context of small sample sizes or rare events, as seen in our review. A random effects model with restricted maximum likelihood (REML) estimation assumes inherent heterogeneity across the study population/ design, which was used to account for between study variability, providing a more conservative estimate. Pooled estimates were reported with 95% confidence intervals (CIs) and visually represented using forest plots. Heterogeneity was assessed using Cochran’s Q test, I² statistic (interpreted as: 0%–40% = low, 30%–60% = moderate, 50%–90% = substantial, and 75%–100% = considerable heterogeneity), between study variance (τ²), and H2. A Galbraith plot was used to explore heterogeneity and detect outliers. If ≥10 studies were available, sensitivity analyses and publication bias assessments (e.g., funnel plot) were planned.

Assessment of the quality of evidence

The certainty of evidence for primary outcomes was assessed independently by two reviewers (KIC and SM) using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, with disagreements resolved by a third reviewer (SP). GRADE is applicable across various study designs, and it evaluates evidence quality based on study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias, overall grading it as high, moderate, low, or very low certainty, reflecting the reviewers’ overall confidence in the effect estimates. Although observational studies typically start as low quality evidence, GRADE allows downgrading for limitations (high risk of bias [e.g., lack of blinding or poor allocation concealment], inconsistency across study findings [I² > 50% heterogeneity], indirectness [e.g., differences in population, intervention, or outcomes], imprecision [e.g., wide CIs due to small sample sizes], and suspected publication bias) or upgrading for factors such as strong effect size, clear dose response, or minimal confounding. These principles enable a nuanced evaluation of observational data, which, although often rated as low or very low quality, may still yield meaningful insights when rigorously assessed. This structured approach supports transparent, evidence based conclusions about TXA in ACEI induced angioedema.

Results

Study selection

A total of 81 studies were identified through PubMed, Scopus, Embase, and ProQuest. After removing 17 duplicates, 64 were screened. Only four studies met the inclusion criteria, all of which were retrospective study (two cohort studies, one retrospective study, and one case series) involving a limited sample size of 133 patients treated with TXA for ACEI induced angioedema.[6 9] The selection process is shown in the PRISMA flow diagram [Figure 1].

Figure 1. PRISMA flowchart for the study selection process

Baseline characteristics of the studies

Three of the four included studies were conducted in the United States. Baseline patient details are shown in Table 1. The face was the most common site of angioedema. In addition to TXA, patients also received H1 and H2 blockers, epinephrine, corticosteroids, FFP, and C1 esterase inhibitor (C1 INH), either prior to or following TXA administration. Lisinopril was used by 79.8% of total patients (257/322) and accounted for 69.2% (92/133) of angioedema cases in the TXA group. The common outcomes assessed in all studies were intubation and ICU admission after TXA treatment.

Table 1. The baseline characteristics, outcome measures and conclusion of the included studies (n=4)

Tablo 1. Contd...

Methodological quality of the included studies

The ROBINS I tool [Figure 2a] showed moderate risk of bias for the observational and cohort studies, whereas the JBI tool [Figure 2b] indicated low risk of bias for the case series. However, both study types are generally considered low or very low quality of evidence.

Figure 2. (a) Risk of bias assessment for observational studies using ROBINS‑I tool (b) Risk of bias assessment for the case series using Joanna Briggs Institute risk of bias tool

Narrative synthesis of tranexamic acid in the treatment of angiotensin converting enzyme inhibitors angioedema

TXA was used to treat ACEI induced angioedema in 133 patients, with doses ranging from 100 mg to 4 g, administered either intravenously (124 patients) or orally (8 patients); the route was unspecified in one case. Fifteen patients out of 133 were intubated, including 8 before TXA administration. In the TXA group, intubation rates were 5.6% (7/125 patients), ICU admission rate was 31.6% (42/133 patients), the mortality rate was 0.75% (1/133 patients), and adverse effects were 0%. Detailed outcomes are presented in Table 1.

Meta analysis

Proportion of patients not requiring intubation post tranexamic acid treatment

This forest plot presents a proportional meta analysis of TXA effectiveness in preventing intubation in ACEI induced angioedema, based on data from four studies [Figure 3a and b]. Using Freeman–Tukey transformation and a random effects REML model, each study’s effect size (transformed proportion) is shown with 95% CIs. Number of successes denotes patients not requiring intubation, total denotes TXA treated patients, blue squares represent point estimates, and the horizontal line represents 95% CI. The green diamond represents the overall pooled proportion, with its center and width indicating the estimate (0.98) and 95% CI (0.91–1.00), suggesting 98% of TXA treated patients did not require intubation.

Figure 3. (a) Proportional meta‑analysis Forest plot on “intubation prevention among angiotensin‑converting enzyme inhibitor (ACEI) induced angioedema post tranexamic acid treatment” (b) Galbraith heterogeneity plot for meta‑analysis assessing the effect of Tranexamic acid (TXA) on prevention of intubation in ACEI‑induced angioedema (c) Proportional meta‑analysis Forest plot on “Non requirement of intensive care unit (ICU) admission post tranexamic acid treatment” (d) Galbraith heterogeneity plot for meta‑analysis assessing the effect of TXA on prevention of ICU admission in ACEI‑induced angioedema

Meta analysis showed moderate heterogeneity (I² = 50.17%, τ² = 0.04, H² =2.01) [Supplementary Table 1]. Although Cochran’s Q test was not statistically significant (Q = 6.03, P = 0.11), the Galbraith plot showed precision dependent heterogeneity. The upward slope suggests studies with greater precision reported a stronger effect size, indicating the possible influence of study level factors, which may explain the variability and should be further explored.

Proportion of patients not requiring intensive care unit admission posttranexamic acid treatment

This forest plot presents a proportional meta analysis of TXA effectiveness in preventing ICU admission in ACEI induced angioedema, based on data from four studies [Figure 3c and d]. Using Freeman–Tukey transformation and a random effects REML model, each study’s effect size (transformed proportion) is shown with 95% CIs. Number of successes denotes patients not requiring ICU admission, total denotes TXA treated patients, blue squares represent point estimates, and the horizontal line represents 95% CI. The green diamond represents the overall pooled proportion, with its center and width indicating the estimate (0.76) and 95% CI (0.58–0.90), suggesting 76% of TXA treated patients did not require ICU admission.

The meta analysis showed significant heterogeneity ((I² = 73.15%, τ² = 0.10, H² = 3.72; Q = 14.41, df = 3, P < 0.00), indicating notable variation across studies [Supplementary Table 2]. The Galbraith plot revealed a positive association between study precision and effect size. The upward slope of the regression line implies higher precision studies reported a stronger effect size. This pattern, along with the significant heterogeneity, highlights the need for cautious interpretation and further investigation into variability, such as differences in study populations or methods.

Grade evidence profile and summary of finding table

The meta analysis suggests a potential benefit of TXA in increasing the likelihood of avoiding intubation (118/125; estimated pooled effect 0.98, 95% CI: 0.91–1.00) and avoiding intensive care admission (91/133; estimated pooled effect 0.76, 95% CI: 0.58–0.90). However, it is crucial to acknowledge the limitations in the available evidence. The certainty of this evidence, assessed using the GRADE system [Table 2], was determined to be low for avoiding intubation and very low for avoiding intensive care admission, reflecting concerns about serious risk of bias in the included nonrandomized studies, inconsistency in results (heterogeneity), and imprecision.

Table 2. Grade evidence profile and summary of findings table for the effect of tranexamic acid on avoiding intubation and intensive care admission

Discussion

TXA is a low cost, widely available antifibrinolytic agent traditionally used to control bleeding in trauma, surgery, hemoptysis, and bleeding disorders. Its potential use in ACEI induced angioedema has gained attention, driven by a deeper understanding of the pathophysiology, which, like hereditary angioedema, both driven by excess bradykinin. Given the bradykinin mediated pathophysiology, TXA has emerged as a promising treatment option due to its safety, accessibility, and ease of administration. While initial evidence supporting TXA was based mainly on case reports and anecdotal evidence, recent retrospective studies have begun to investigate its efficacy. However, despite growing interest, only one comparative study has assessed TXA against a control group, and no RCTs have been conducted to date.

Mechanism and clinical application

ACE normally degrades bradykinin. Thus, ACEI leads to bradykinin accumulation, leading to angioedema.[10-13] TXA, an antifibrinolytic agent, has been proposed as a treatment option due to its ability to inhibit the conversion of plasminogen to plasmin formation.[14 16] Plasmin plays a role in the Kallikrein–Kinin system, contributing indirectly to bradykinin generation. Thus, TXA prevents activation of Kallikrein, a crucial enzyme in the bradykinin cascade. This ultimately leads to a reduction in bradykinin production. Bradykinin is a potent vasoactive peptide responsible for vasodilation and increased vascular permeability, which contribute to angioedema. By attenuating this pathway, TXA may help reduce bradykinin mediated vascular leakage and edema.[17]

Tranexamic acid efficacy, safety, and potential confounders

TXA was administered primarily through the intravenous route (93.2% of cases), with doses ranging from 100 mg to 4 g; though oral administration was reported in few. Key outcomes assessed included hospital length of stay, ICU admissions, intubation, and mortality. Across studies, no TXA related adverse events and a low mortality rate (0.75%) were reported, suggesting a potential safety profile. However, clinical outcomes are likely influenced by several variables, including TXA dose, route, timing, patient characteristics (e.g., age, race, and severity), concurrent therapies, and study setting. Frequent use of concurrent therapies, such as corticosteroids, antihistamines, epinephrine, icatibant, FFP, and C1 INH, introduces significant confounding. In some studies, TXA was preferentially used in patients with more severe symptoms, further complicating comparisons. These factors limit the ability to attribute outcomes solely to TXA and highlight the need for cautious interpretation and further controlled trials.

Several off label therapies used for ACEI induced angioedema are derived from hereditary angioedema treatments, including icatibant, ecallantide, FFP, and C1 INH. While icatibant and ecallantide show mixed efficacy and are limited by high cost and availability, FFP offers a more accessible and cost effective option despite safety concerns. C1 INH has shown promise in case reports, but a lack of clinical trials and limited emergency access restrict its use. Importantly, no direct studies compare these agents with TXA, limiting evidence.

Clinical/methodological/statistical heterogeneity

Clinical heterogeneity across studies was evident, reflecting differences in patient demographics, ACE inhibitor types, TXA dose, route, timing, and concurrent treatments. Methodological variability, including differences in study design, sample size, and outcome definitions, further contributed to inconsistency. Frequent use of cointerventions – such as corticosteroids, H1/H2 blockers, epinephrine, FFP, and C1 INH – introduced additional confounding. These factors likely underlie the moderate to high statistical heterogeneity observed and support cautious interpretation of pooled results.

Meta analysis findings

The efficacy of TXA in preventing intubation and ICU admission in ACE inhibitor induced angioedema was analyzed across four studies. The pooled proportion of patients not requiring intubation was 0.98 (95% CI: 0.91– 1.00), with moderate heterogeneity (I² = 50.2%, P = 0.11). For ICU admission, 76% did not require ICU care (95% CI: 0.58–0.90), though substantial heterogeneity was present (I² = 73.15%, P < 0.00), reflecting differences in study populations and methods.

Implications for clinical practice

TXA may be a potentially effective and accessible treatment for ACEI induced angioedema, with reported doses ranging from 100mg to 4 g given(most common 1 g) via intravenously or orally. Preliminary findings suggest that TXA may possibly reduce the need for intubation and ICU admissions in patients. Although TXA is widely available, low cost, and showed no reported adverse effects in the included studies, the supporting evidence is limited and of very low quality due to retrospective design, bias, and inconsistency. Although TXA may be a potential early treatment option,[18 22] robust RCTs are needed to confirm its efficacy and safety.

Recommendations for future research

This review underscores the lack of high quality evidence on TXA for ACEI induced angioedema, with only a few retrospective studies and no RCTs to date. Future research should focus on well powered RCTs and prospective multicenter studies to better assess TXA’s efficacy and safety. These studies should focus on optimal dosing, treatment duration, administration route, dose frequency, and standardized outcomes such as symptom resolution time, hospital/ICU stay duration, intubation rates, and recurrence. Evaluating adverse effects across diverse populations is also vital to inform clinical guidelines and decision making. Apart from TXA, no direct comparative studies have been conducted between different agents for ACEI induced angioedema. Future research is needed to facilitate more comprehensive comparisons of efficacy and adverse effects, ultimately aiding in the selection of the most appropriate treatment.[11]

Limitation and strength

This systematic review is among the first to assess TXA for ACEI induced angioedema, based on a comprehensive search across multiple databases. However, the overall evidence quality is low, with all studies being retrospective, primarily observational, and case series, with no RCTs. Most were single arm studies, lacking a comparison group, except one which limits the robustness of findings. The small sample size (133 patients) reduces generalizability, and moderate to substantial heterogeneity reflects variability in patient profiles, TXA dosing, timing, and co treatments. The absence of standardized TXA protocols and frequent use of concurrent therapies confound interpretation. Long term efficacy, recurrence, and safety data remain limited. The literature search was last updated in February 2025, so studies published after that may not have been captured. Limited data precluded subgroup analysis. Publication bias could not be assessed due to the limited (<10) studies.

Conclusion

TXA may be a potential treatment option for angioedema induced by ACEIs. Our review indicates a possible association between TXA use and reduced rates of intubation and ICU admission in these patients. However, this finding is based on retrospective data, and the lack of RCTs limits the strength of the evidence. Confounding from concurrent therapies and variability in TXA use warrant cautious interpretation. Given these significant gaps, more robust prospective and RCTs are needed to draw firmer conclusions about the efficacy and safety of TXA in ACEI induced angioedema and to guide clinical decision making.

Supp. T. 1. Proportional meta‑analysis on “Nonrequirement of intubation posttranexamic acid treatment

Supp. T. 2. Proportional meta‑analysis on “Nonrequirement of intensive care unit admission posttranexamic acid treatment

How to cite this article: Couppoussamy KI, Mahalingam S, Rajendran G, Purushothaman S, Ramkumar A, Krishnamoorthy Y, et al. Effect of tranexamic acid in the treatment of angiotensin‑converting enzyme inhibitor‑induced angioedema: Asystematic review and meta‑analysis. Turk J Emerg Med 2026;26:45-54.

Not applicable.

SM, KIC: Conceptualization (lead), Resources (lead), Writing‑original draft(lead), Writing, Reviewing and Editing (lead), Visualization (lead). SP, GR, AR: Conceptualization (equal), Writing Reviewing, and Editing (equal). YK, EG, and AK: Writing Review and Editing (Supporting).

None Declared.

None.

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