Tranexamic acid for angiotensin converting enzyme inhibitor induced angioedema: A retrospective multicenter study

Authors: Kristen E. Lindauer, PharmD, BCPS; Bruce M. Lo, MD, MBA; Gregory S. Weingart, MD; Matvey V. Karpov, MPH; Grace H. Gartman, MD

Journal: American Journal of Emergency Medicine

Year: 2024

Volume: 79

Type of Study: Retrospective multicenter cohort study

DOI: 10.1016/j.ajem.2024.02.006

Quick Reference Summary

Key Findings: Administration of tranexamic acid in patients with ACE-I induced angioedema was associated with a significantly longer emergency department (ED) length of stay (LOS) (median 20.9 hours vs. 4.8 hours, p < 0.001) and higher rates of ICU admissions (45% vs. 16%, p < 0.001) and intubations (12% vs. 3%, p = 0.018) compared to controls.

Main Results: No differences were observed between groups for 7-day ED return rates, thrombosis-related complications, or mortality.

Core Clinical Question

Primary Research Question: Does the administration of tranexamic acid reduce length of stay and improve patient-centered outcomes in adults presenting to the emergency department with ACE inhibitor-induced angioedema compared to standard treatment without tranexamic acid?

Background

Disease Overview

Angioedema is a swelling of the deeper layers of the skin, often affecting the face, lips, tongue, and airway, and can be life-threatening when it involves the airway. Approximately 0.1–0.7% of patients on angiotensin-converting enzyme inhibitors (ACE-Is) develop ACE-I induced angioedema (ACE-IIA), with African Americans at a fourfold higher risk.

Prior Data:

Pathophysiology: ACE-Is inhibit the breakdown of bradykinin, leading to increased vascular permeability and angioedema.

Treatment Standard: Current management includes discontinuing the offending ACE-I and administering antihistamines, steroids, and/or epinephrine, though there is no evidence supporting their effectiveness in ACE-IIA.

Current Standard of Care

Standard treatment involves supportive care with antihistamines, steroids, and epinephrine, despite limited evidence for their efficacy in bradykinin-mediated angioedema.

Knowledge Gaps Addressed

Lack of evidence on the effectiveness of tranexamic acid, an antifibrinolytic agent that inhibits bradykinin synthesis, in treating ACE-IIA.

Study Rationale

To evaluate whether tranexamic acid can reduce LOS and improve outcomes in ACE-IIA patients presenting to the ED.

Methods Summary

Study Design: Retrospective multicenter cohort study.

Setting and Time Period: Seventeen emergency departments within an integrated health system across two states, from January 1, 2018, to August 31, 2021.

Population Characteristics: Adults aged 18–89 years presenting with ACE-I induced angioedema.

Inclusion/Exclusion Criteria:

• Included: Patients with a diagnosis of angioedema and an active prescription for an ACE-I.
• Excluded: Patients presenting only with urticaria, angioedema from other causes, history of hereditary angioedema, or incomplete medical records.

Intervention Details: Administration of tranexamic acid (initial dose of 1000 mg, range 1000–2000 mg; additional doses in 5 patients up to 3000 mg).

Control/Comparison Group: Patients with ACE-I induced angioedema who did not receive tranexamic acid.

Primary and Secondary Outcomes:

• Primary Outcome: Length of stay (LOS) in the ED.
• Secondary Outcomes: ICU admissions, need for intubation, 7-day ED return, thrombosis-related complications, and mortality.

Statistical Analysis Approach: Descriptive statistics, univariate analyses (t-tests, Mann-Whitney U, Chi-square, Fisher's Exact tests), and multivariate regression models controlling for independent variables and angioedema severity.

Sample Size Calculations: Not explicitly detailed.

Ethics and Funding Information: Approved by the Eastern Virginia Medical School Institutional Review Board. No specific funding sources; no conflicts of interest reported.

Detailed Results

Participant Flow and Demographics

• Total Patients Included: 262 (73 treatment; 189 control).
• Average Age: 59 years;
• Gender: 50.0% males;
• Race: 70.6% African Americans.
• Angioedema Severity: Stage 1 more common in controls (34.3% vs. 16.5% in treatment); Stage 3 more common in treatment group (42.5% vs. 26.5% in controls).

Primary Outcome Results:

• ED Length of Stay:
  • Treatment Group: Median 40.28 hours (IQR: 49.20)
  • Control Group: Median 21.08 hours (IQR: 14.30)
  • Difference: p < 0.0001
  • Effect Size: LOS was 40.1% longer in the treatment group (p = 0.032, 95% CI: 28.8–64.5%).

Secondary Outcome Results:

• ICU Admissions:
  • Treatment: 45.2%
  • Control: 15.9%
  • Difference: p < 0.0001
• Intubations:
  • Treatment: 12%
  • Control: 3%
  • Difference: p = 0.018
• 7-Day ED Return:
  • Treatment: 2.7%
  • Control: 5.3%
  • Difference: p = 1
• Thrombosis Events: 0 in both groups.
• Mortality:
  • Treatment: 1.4%
  • Control: 0.5%
  • Difference: p = 0.48

Subgroup Analyses:

In patients with Ishoo Stage 2, 3, or 4 angioedema, no significant difference in LOS between treatment and control groups (p = 0.247).

Results Tables

Authors' Conclusions

Primary Conclusions: Tranexamic acid administration in ACE-I induced angioedema patients was associated with longer ED LOS, higher rates of ICU admission, and increased need for intubation.

Interpretation of Results: The increased LOS and severity indicators in the treatment group may reflect more severe presentations rather than an adverse effect of tranexamic acid.

Clinical Implications: Tranexamic acid appears safe for use in ACE-IIA but does not demonstrate efficacy in reducing LOS or improving other patient-centered outcomes in this retrospective study.

Future Research Recommendations: Prospective randomized controlled trials are necessary to determine the effectiveness of tranexamic acid in treating ACE-I induced angioedema.

Literature Review

Comparative Studies:

• Previous Case Reports: Showed resolution of angioedema symptoms within 2–8 hours with tranexamic acid.
• Current Study Findings: Contradict case reports, showing longer LOS with tranexamic acid use.

Guidelines and Recommendations:

Existing guidelines focus on antihistamines, steroids, and epinephrine without addressing tranexamic acid.

Meta-Analyses and Systematic Reviews:

Tranexamic acid associated with minimal risk of thromboembolic events in other contexts.

Critical Analysis

A. Strengths

• Multicenter Design: Included seventeen EDs across two states, enhancing external validity.
• Sample Size: Included a relatively large cohort of 262 patients.
• Comprehensive Data Collection: Utilized electronic medical records with multiple reviewers to ensure consistency.
• Detailed Outcome Measures: Evaluated both primary and multiple secondary outcomes, including safety data.

B. Limitations

• Retrospective Design: Subject to selection bias and confounding factors.
• Severity Imbalance: Treatment group had more severe angioedema presentations, potentially confounding LOS and ICU admission rates.
• Incomplete Data Capture: Lack of information on pre-ED medications and history of venous thromboembolism.
• Single Health System: Limits generalizability to other settings with different protocols.
• Potential Documentation Errors: Reliance on EMR for symptom severity and medication administration timing.

C. Literature Context

A. Previous Studies and Meta-Analyses:

• Case Reports: Tranexamic acid led to symptom resolution within hours.
  Am J Emerg Med. 2021;43:292.e5–7.
• Trauma Studies: No clotting events observed with tranexamic acid use.
  JAMA Surg. 2018;153(2):169–75.

B. Contrasting Methodological Quality:

• Current Study: Retrospective cohort with potential confounders.
  This study.
• Case Reports: Limited by anecdotal nature and lack of control groups.
  Am J Emerg Med. 2021;43:292.e5–7.

C. Comparisons with Guidelines:

• Current Guidelines: Recommend antihistamines, steroids, and epinephrine for ACE-IIA.
  Acad Emerg Med. 2014;21:469–84.

D. This Trial's Contribution:

• Adds to Evidence: First multicenter study evaluating tranexamic acid for ACE-IIA.
• Contradicts Case Reports: Did not find reduced LOS or improved outcomes.
  Ann Allergy Asthma Immunol. 2008;100:327–32.

Clinical Application

Practice Implications: Tranexamic acid should not be routinely used for ACE-I induced angioedema based on current evidence, as it does not reduce LOS and is associated with more severe outcomes.

Applicable Scenarios: In cases of severe angioedema (Ishoo Stage 2-4), tranexamic acid does not appear to impact LOS or need for ICU admission, suggesting no benefit in this subgroup.

How to Use This Info In Practice

Recommendation for Practitioners: Tranexamic acid administration for ACE-I induced angioedema is not supported by current evidence and should be considered on a case-by-case basis until further research is available.