Angiotensin-converting enzyme inhibitors (ACE-I) are medications within the antihypertensive class that are used by nearly 108 million patients worldwide [1]. A rare but possibly life-threatening adverse effect of ACE-I is angioedema, which occurs due to elevated levels of bradykinin [2]. In this case report, we discuss a patient case where the use of tranexamic acid (TXA), an antifibrinolytic agent, prevented impending intubation due to ACE-I induced angioedema.
While ACE-AE is rare, unfortunately, it is estimated that between 0.1 to 0.7% of patients on ACE-I develop angioedema [2]. This arises most commonly within the first year of treatment. However, it may also develop after years of use. Angioedema presents as asymmetric swelling of the face, lips, larynx, genitalia, or extremities. It occurs due to elevated levels of bradykinin, leading to vasodilation of blood vessels, increased vascular permeability, and plasma extravasation into the submucosal tissue. The most severe cases include failure to secure the airway requiring intubation [4]. There are also some genetic and environmental risk factors for development of ACE-AE. These include age over 65, African American decent, smoking, and history of ACE-I induced dry cough [6,7].
Currently, there is no standard treatment for ACE-AE. Typical first line management includes a combination of histamine targeted therapies (e.g. epinephrine, antihistamines, and corticosteroids), which are likely ineffective.5 Intubation is also considered as swelling of the mucosa can lead to airway obstruction with concomitant hypoxia and potentially death. Fresh frozen plasma (FFP), icatibant, and ecallantide have all been explored in the use of ACE-AE. FFP contains ACE which can catalyze the degradation of excessive bradykinin [8]. Icatibant, a selective antagonist of the bradykinin β2 receptor, was shown in a phase II trial to decrease the time of complete resolution of ACE-AE when compared to antihistamine and corticosteroid therapy [9]. Ecallantide, a plasma kallikrein inhibitor, was studied in another phase II trial where it was thought to decrease ACE-AE by inhibiting kallikrein, the enzyme responsible for converting kininogen to bradykinin [10]. Both icatibant and ecallantide are well studied in the treatment of hereditary angioedema (HAE), which are associated with C1esterase inhibitor deficiency [5]. However, the uses of these bradykinin targeted therapies are limited in ACE-AE due to cost and efficacy [11].
A more novel approach in the acute management of ACE-AE involves TXA. As seen in Figure 1, TXA inhibits the conversion of plasminogen to plasmin, which is responsible for activating factor XII to factor XIIa. Factor XIIa stimulates kallikrein activation and cleaves kininogen, which produces bradykinin [4,6]. By reducing the amount of bradykinin, TXA can improve ACE-AE and prevent impending intubation. The average cost of TXA for 1g is $6, which makes this pharmacotherapy significantly more affordable compared to treatment options like icatibant and ecallantide [12].
Currently, there are no large, randomized, controlled trials published regarding the use of TXA in ACE-AE. However, there are limited retrospective studies and case reports justifying its role in. In 2010, a retrospective study analyzed the treatment of TXA given to 25 patients for sporadic idiopathic bradykinin angioedema. It was found that 18 patients had complete remission of symptoms, corresponding to 72%, after administration of TXA [13]. Another retrospective observational study in 2014, which included 37 patients who had either HAE or idiopathic non-histaminergic angioedema, reported that an average of 2.5g of tranexamic acid taken for six months was able to reduce the number of angioedema attacks by 75% [14]. Lastly, a 2018 retrospective review reported improvement in 27 of the 33 patients studied with ACE-AE after receiving 1 gram of TXA within 1 hour of symptom onset. In this review, none of the patients required intubation [15].
Our case report shows that TXA is a cost effective antifibrinolytic agent that reduces the symptoms of ACE-AE. The effect seen in our case is confounded by the concomitant use of histamine targeted therapies. However, TXA was considered only after the patient failed to show improvements with the aforementioned therapies.