Ticagrelor Induced Angioedema Following Carotid Artery Stenting

Abstract

Ticagrelor is a frequent component of dual antiplatelet therapy (DAPT) following carotid artery stent placement. Hemorrhagic complications remain the focus of most reports, however, other adverse events must also be known to the prescribing physician. Angioedema is a rare and potentially life-threatening complication reported following ticagrelor administration and we present 1 such case here with a review of the existing literature.

Introduction

Dual antiplatelet therapy (DAPT) is a standard therapy following carotid artery stenting to prevent stent thrombosis. ¹ Multiple different P2Y12 inhibitors are used in combination with aspirin as a part of DAPT after stent placement. Ticagrelor is 1 such agent chosen specifically in patients considered to be non-responders to clopidogrel. ² As a non-thienopyridine P2Y12 inhibitor, it binds as a reversible, noncompetitive inhibitor of the P2Y12 receptor leading to inhibition of platelet activation and aggregation. Ticagrelor has been demonstrated to have more potent inhibition of the P2Y12 receptors when compared to clopidogrel without an increase in the risk of hemorrhagic complications. ³ In addition to the bleeding risk associated with the use of antiplatelets, allergic reactions are not uncommon. Ticagrelor has been reported to cause a rare hypersensitivity reaction in the form of rash. ⁴ Here, we report the case of a patient admitted with ischemic stroke undergoing mechanical thrombectomy and carotid artery stent placement with subsequent development of angioedema following initiation of ticagrelor.

Case Presentation

A 76 years-old African American man with past medical history significant for atrial fibrillation not currently on anticoagulation, coronary artery disease with prior bypass graft, mitral valve replacement, and hypertension presented with sudden onset of aphasia and right sided weakness. His symptoms began without a precipitating event approximately 30 minutes prior to his presentation to the emergency department.

Physical examination was consistent with a left middle cerebral artery (MCA) syndrome; marked by global aphasia, right homonymous hemianopia, right sided facial droop, left gaze preference, right sided weakness, and sensory loss. His NIH stroke scale score was 21 on arrival to the emergency department. Initial blood pressure measured as 209/110 mmHg with an irregularly irregular heart rhythm. Initial blood glucose was reported as 109. Computed tomography (CT) of the head demonstrated a hyperdense left MCA sign with Alberta Stroke Program Early CT (ASPECT) score of 8. Intravenous alteplase, .09 mg/kg bolus followed by .81 mg/kg infusion, was administered prior to CT angiogram that revealed the left internal carotid (ICA) and proximal left MCA were occluded. The alteplase infusion completed without evidence of new bleeding or the development of angioedema noted by nursing or bedside providers. Successful mechanical thrombectomy was completed achieving TICI 3 recanalization following placement of a left internal carotid artery stent. The patient was placed on eptifibatide drip .5 mcg/kg/min during the procedure. Post-treatment imaging demonstrated a large infarct in the distribution of the left MCA territory on Magnetic Resonance Imaging (MRI).

The patient remained intubated following the procedure and was admitted to the neurointensive care unit where he received a dose of aspirin 325 mg and ticagrelor 60 mg. Therapy was transitioned to aspirin 81 mg daily and ticagrelor 60 mg twice daily on post-intervention day 1. One day following initiation of DAPT, he developed obvious and significant tongue and lip swelling that continued to worsen over the following 5 days. Initially, the angioedema was suspected to be a result of chlorhexidine swabs as routinely used in antiseptic care which was discontinued and flagged as an allergy. There was persistent swelling after the discontinuation of chlorhexidine. Given the significant degree of angioedema and post-stroke aphasia he remained endotracheally intubated to protect his airway. Discussion focused on the patient’s continued angioedema resulted in a transition of ticagrelor to clopidogrel on post-stroke day 6 after which there was significant documented improvement in swelling of both the tongue and lips.

Discussion

Tongue and lip swelling presents as a potentially life-threatening scenario. Early recognition of its occurrence and etiology is necessary to avoid catastrophic acute and chronic complications. Both hereditary and acquired etiologies of angioedema are known to exist. Acquired angioedema may be mediated by immunologic, non-immunologic, or idiopathic mechanisms. ⁵ Generally it is characterized by repetitive episodes of swelling where fatality is possible when the swelling goes unnoticed or involves the respiratory tract. Angioedema pathophysiology is thought to be secondary to an accumulation of bradykinins, leading to the administration of antihistamines, intravenous steroids, and cessation of any potential inciting medication as the mainstay of therapy. ⁵ Rescue treatment with epinephrine should be considered in severe cases associated with anaphylaxis or airway obstruction. In some cases, patients may require tracheal intubation or emergency cricothyrotomy to prevent respiratory arrest as a result of hypoxia that occurs secondary to the progression of laryngeal edema. ⁶

Drug induced angioedema is rare and is only estimated to be the cause in less than 1% of cases. ⁶ Multiple medications prescribed in the setting of acute neurologic illness have been implicated as etiologies of angioedema and include angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aspirin, non-steroidal anti-inflammatories, streptokinase, and alteplase. The incidence of tissue plasminogen activator (tPA) induced angioedema is reported to be upwards of 5% in a study by Hill et al. When angioedema does occur following treatment of stroke with tPA it typically occurs during or within 2 hours of the infusion and is more frequently observed in patients treated concomitantly with angiotensin-converting enzyme (ACE) inhibitors. ⁷

Ticagrelor is an additional medication used during acute neurologic illness that has been reported as an etiology of sudden onset angioedema. In our review of the literature there have been only 2 published cases implicating Ticagrelor as the underlying cause of angioedema.^8,9 In both cases, angioedema occurred within 72 hours of exposure, as was the case for the patient described here.

Determining the likelihood that a clinical manifestation is related to an adverse drug reaction is often subjective and controversial, even among members of the clinical team. Multiple scales have been developed over time to improve the validity of these claims. Two in particular that have demonstrated consistent agreement and ease of use are the Yale and Naranjo algorithms. ¹⁰ These 2 algorithms have been shown to be reproducible and more consistent than clinical judgement alone and are used by many clinical pharmacists to assess with determinations of risk for drug reactions.

In the case presented above, our patient was not on angiotensin converting enzyme inhibitors or any other medication previously associated with the development or risk for development of angioedema. Our patient did receive alteplase in the emergency department as part of the acute management for his stroke but was not reported to develop any signs of hypersensitivity. Signs and symptoms of angioedema were not present until 24-hours after having started on DAPT with ticagrelor. Following the transition of ticagrelor to clopidogrel a significant improvement was noted in both tongue and lip swelling suggesting the ultimate etiology was related to ticagrelor use. Aspirin can also cause angioedema, however it is less likely in our case given the significant improvement in tongue and lip swelling after ticagrelor discontinuation. In this case ticagrelor was found to have a Naranjo ¹¹ adverse drug reaction probability score of 5 and a Yale ¹² adverse drug reaction score of 4, indicating a probable adverse event of angioedema resulting from ticagrelor initiation.

Conclusion

Here we present a case of ticagrelor-induced angioedema. This rarely noted adverse effect of ticagrelor should be recognized by all healthcare providers caring for patients started on DAPT. While this patient did not suffer significant airway compromise due to continued endotracheal intubation, it is likely that emergent, and possibly difficult, intubation would have been required should he have experienced this side effect with only his native airway and been unable to express developing respiratory distress in the setting of his acute stroke. This case report demonstrates the need to improve individualized medication selection for DAPT and potential for monitoring parameters after initiation of DAPT following carotid artery stent placement.

ORCID iDs

Ahmed Elmashad https://orcid.org/0000-0003-4443-2721

Allison Gorseth https://orcid.org/0000-0002-9960-5274