What is the recommended pharmacological treatment for tenecteplase-induced angioedema?

Comment by InpharmD Researcher

Though specific to alteplase-induced angioedema, clinical guidance suggests use of pharmacological management with famotidine, antihistamines, and corticosteroids, use of which are reflected in a limited number of case studies reporting tenecteplase-induced angioedema. In the event of increased angioedema, epinephrine may be administered. Plasma-derived C1 esterase inhibitor has also been observed to resolve symptoms. However, other experts suggest consideration of bradykinin-reducing agents (e.g., icatibant) as initial treatment in order to target the bradykinin pathway instead of the histamine pathway.

Background

The 2019 American Heart Association/American Stroke Association guideline update provides evidence-based recommendations for the early management of acute ischemic stroke, building upon and revising the 2018 guideline. While the document addresses a broad range of diagnostic and therapeutic issues, it also highlights the management of orolingual angioedema, a recognized complication of intravenous alteplase, particularly in patients concurrently taking angiotensin-converting enzyme inhibitors. The guideline emphasizes airway protection as the foremost priority, recommending endotracheal intubation if swelling involves the larynx, palate, or oropharynx, especially in the setting of rapid progression. For milder cases limited to the anterior tongue or lips, close observation may be appropriate. Alteplase infusion should be discontinued, and angiotensin-converting enzyme inhibitors withheld. Pharmacologic management includes intravenous methylprednisolone, diphenhydramine, and an H2 receptor antagonist such as ranitidine or famotidine. In cases of progression, subcutaneous or nebulized epinephrine may be employed. Targeted therapies such as icatibant, a bradykinin B2 receptor antagonist, or plasma-derived C1 esterase inhibitor have been used in related types of angioedema, although data in the alteplase setting are limited. Supportive care remains essential throughout management. Of note, these recommendations are primarily based on expert opinion and case experience rather than high-quality randomized trials, and are not specific to tenecteplase-associated angioedema. [1]

A 2024 analysis explores the pathophysiological mechanisms of angioedema induced by recombinant tissue-type plasminogen activators (r-tPA) such as alteplase and tenecteplase in stroke patients. The authors argue that this condition is primarily mediated by bradykinin rather than histamine, a hypothesis that shifts the conventional understanding of this complication. They highlight the clinical efficacy of bradykinin receptor antagonists like icatibant and C1 inhibitor concentrate in treating r-tPA-induced angioedema, which contrasts with the limited effectiveness of antihistamines, epinephrine, and steroids. This perspective is further supported by data showing that patients on angiotensin-converting enzyme (ACE) inhibitors, which increase systemic bradykinin levels, have a higher risk of developing angioedema post-r-tPA treatment, as well as other adverse symptoms associated with r-tPA therapy, such as hypotension and urticaria. Although historically interpreted as allergic reactions, these symptoms could also arise from elevated bradykinin levels leading to increased vascular permeability and vasodilatation. The authors propose a treatment paradigm shift where r-tPA-induced angioedema should be initially managed by targeting the bradykinin pathway rather than the histamine pathway, using bradykinin pathway inhibitors as first-line treatment to prevent fatal outcomes potentially associated with r-tPA-induced angioedema. [2]

References:

[1] Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418. doi:10.1161/STR.0000000000000211
[2] Hutten EM, van de Ven AAJM, Mencke R, Pleijhuis RG. Angioedema After Use of Recombinant Tissue-Type Plasminogen Activators in Stroke. Stroke. 2024;55(8):2193-2197. doi:10.1161/STROKEAHA.124.047060
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the recommended pharmacological treatment for tenecteplase-induced angioedema?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

 

Tenecteplase-associated orolingual angioedema: A case report and literature review

Design

 Case report

Case presentation

 A 67-year-old white male with a history of hypertension, hyperlipidemia, and diabetes presented with symptoms consistent with an acute ischemic stroke. Forty-five minutes after receiving tenecteplase (25 mg given as intravenous push [IVP] over 10 seconds), the patient developed orolingual angioedema (OA), characterized by nonpruritic and nonpitting swelling localized to the face and oropharyngeal area. Despite initial treatment with antihistamines (diphenhydramine 25 mg IVP), corticosteroids (dexamethasone 25 mg IVP), famotidine 20 mg, and subsequent administration of a C1 esterase inhibitor (Berinert 20 mg/kg as IV piggyback, for a total dose of 2,500 units), the patient's symptoms progressed, necessitating endotracheal intubation to secure the airway. To prevent refractory angioedema, methylprednisolone 40 mg IVP every 12 hours, famotidine 40 mg IVP every 12 hours, and diphenhydra- mine 25 mg IVP every 6 hours were initiated. The patient was eventually extubated after 30 hours, and was discharged on day 4.

Study Author Conclusions

Although rare, OA is a potentially life-threatening compli-cation of tenecteplase therapy and requires prompt pharmacologicalintervention to optimize patient outcomes. Currently, no single agent ortreatment algorithm exists that has shown significant efficacy or safetyin the setting of thrombolytic-associated OA. Until data are available forC1 esterase inhibitors in this application, these inhibitors should only beconsidered if there is continued symptom progression after intravenousadministration of corticosteroids and antihistamines.

 

References:

Pitts JK, Burns DM, Patellos KR. Tenecteplase-associated orolingual angioedema: A case report and literature review. Am J Health Syst Pharm. 2024;81(9):e220-e225. doi:10.1093/ajhp/zxad334

 

Bradykinin-Mediated Angioedema Following Tenecteplase Administration in an Acute Ischemic Stroke

Design

 Case report

Case presentation

An 81-year-old man was administered tenecteplase for a right posterior cerebral artery ischemia. One hour following administration, the patient presented with angioedema, charcterized by lingual swelling and sudden oxygen desaturation. Therapy with C1 inhibitor concentrate resolved symptoms rapidly. Notably, dosage of tenecteplase was not discussed.

Study Author Conclusions

 Care should be taken with tenecteplase and the use of C1 inhibitor concentrate should be considered if bradykinin-mediated angioedema occurs.

 

References:

Lapostolle A, Wesisenburger-Lile D, Yger M, et al. Bradykinin-mediated angioedema following tenecteplase administration in an acute ischemic stroke. Stroke. 2022;53(10):e446-e447. doi:10.1161/STROKEAHA.122.040052

 

A Novel Approach to the Treatment of Orolingual Angioedema After Tissue Plasminogen Activator Administration

Design

  Case Report

Case presentation

A 72-year-old man with a medical history of coronary artery disease, prior myocardial infarction with stent placements, hypertension, and hyperlipidemia presented with acute right-sided weakness and dysarthria, corresponding to a National Institutes of Health Stroke Scale score of 10. Following the diagnosis of acute ischemic stroke, he received intravenous tissue plasminogen activator (tPA) and subsequently developed tongue swelling consistent with orolingual angioedema, which was initially treated with intravenous diphenhydramine during transfer to a comprehensive stroke center. On arrival to the intensive care unit, the angioedema worsened, and he received methylprednisolone, famotidine, and additional diphenhydramine for symptomatic relief.

Given concerns about airway compromise and the challenges of airway management after recent thrombolysis, plasma-derived C1 esterase inhibitor (1,500 IU) was administered, resulting in improvement of tongue swelling and avoidance of intubation or cricothyrotomy. Laboratory evaluations before and after treatment, including C1 esterase inhibitor levels and function, C4 binding protein, C4 complement, and tryptase, were within normal limits, excluding deficiency or dysfunction. Despite successful management of angioedema, the patient experienced neurological decline six hours after tPA administration due to bilateral posterior parietal lobe intraparenchymal hemorrhages, a known complication of thrombolysis, followed by malignant cerebral edema attributed to stroke or hemorrhage, with no evidence in the literature linking C1 esterase inhibitor therapy to hemorrhage.

Study Author Conclusions

Standard anaphylaxis treatments, including supportive care, corticosteroids, epinephrine, and histamine antagonists, are often employed to manage symptoms and control the progression of angioedema. When there is significant airway obstruction that might require an emergency airway intervention. A C1 esterase inhibitor is suggested as a possible treatment option for patients experiencing tPA-induced orolingual angioedema with airway compromise that does not respond to standard care.

The extent of applicability to tenecteplase-induced angioedema is uncertain.

 

References:

Pahs L, Droege C, Kneale H, Pancioli A. A Novel Approach to the Treatment of Orolingual Angioedema After Tissue Plasminogen Activator Administration. Ann Emerg Med. 2016;68(3):345-348. doi:10.1016/j.annemergmed.2016.02.019