Angioedema: a previously unreported adverse effect of Apixaban (Eliquis)

 

Article By

 

Mohammad Umar Farooq

Daniel Mascarenhas

 

Abstract

92-year-old  male  with  past  medical  history  for  paroxysmal  atrial  fibrillation  and  sick  sinus syndrome s/p dual chamber pacemaker was maintained in sinus rhythm with sotalol. Prior attempts at anticoagulation with warfarin lead to spontaneous hematoma in the upper extremity leading to discontinuation  of the drug. He was started on apixaban renally dosed at 2.5 mg oral twice daily. However, the next morning he subsequently developed periorbital facial edema, circumoral pruritis, symmetric swelling of his oral mucosa and tongue. Suspecting a hypersensitivity reaction, apixaban was discontinued. The following morning all signs of swelling and pruritis had resolved without the use of corticosteroids. This case demonstrates the unusual occurrence of angioedema with apixaban.

 

Introduction:

Apixaban, brand name Eliquis, is an anticoagulant indicated for non-valvular atrial fibrillation.   It works via inhibition of factor Xa. It is approved for prevention of cerebrovascular events in non-valvular atrial fibrillation. The ARISTOTLE trial demonstrated superiority of apixaban vs. warfarin  in  three  key outcomes  –  stroke  and systemic embolism, major bleeding, and all-cause mortality  for  patients  with  non-valvular atrial fibrillation[1].

Case Description:

A 92 year old male patient was admitted for acute bacterial pneumonia.    Additionally, he  carried a past medical history of paroxysmal atrial fibrillation, sick sinus syndrome with subsequent dual-chamber right-sided permanent pacemaker implantation.   Prior attempts of anticoagulation with warfarin resulted in the patient developing a large spontaneous hematoma in the upper extremity, causing discontinuation of the drug. He was also treated with 80mg of sotalol thrice daily, which maintained him in normal sinus rhythm, and 81mg of enteric coated aspirin.

His CHADS VASC score was calculated to be 4, yielding a 4% risk of a cerebrovascular event[2]. The patient was started on apixaban 2.5mg twice daily.   The first dose was administered  at 2pm without significant initial side effects. However, the following morning, it was found that he had symmetric swelling of his lips, buccal mucosa, and tongue, as well as circumoral pruritis.   The apixaban      was     immediately      discontinued as angioedema was suspected.   He had no concomitant stridor, hoarseness of voice, rashes, or prior similar episodes.  Other aspects of his medical history did not reveal any prior allergic or  anaphylactic reaction.    The  patient  had  no additional food or medication allergies. Physical exam showed a blood pressure of 106/63, heart rate 95 bpm, respiratory rate 22/min, temperature 98.8  degrees Fahrenheit, and   pulse   oximetry 91% on room  air.   He was in no acute distress and  inspection  of his face revealed symmetric edema of his lips, tongue, sublingual soft tissues, and  buccal mucosa. He had peri-orbital facial edema and pharyngeal edema.   He was not dyspneic.   Auscultation  of the  posterior  lungs revealed no rales or wheezes. The remainder of the physical exam was essentially benign.   The patient  did not  receive any additional  systemic corticosteroids.

The following morning, the periorbital swelling had markedly subsided.  The following day, his symptoms had completely resolved.

Discussion:

Angioedema is not a commonly mentioned possible side effect of apixaban, or Eliquis.  The Naranjo probability scale indicates that the time course of the patient’s symptoms and subsequent prompt  resolution  with  discontinuation  of the drug makes this adverse drug event probable[3].

Angioedema, or rapid swelling of the skin and submucosal tissue, is a potentially life-threatening condition. Most commonly involving the lips, tongue, face, hands and feet, it is often mediated by allergy, emotional stress, and local trauma.  The well-defined inherited form known as hereditary  angioedema  is due  to  deficiency and abnormal function of C1 esterase inhibitor.

In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism while also decreasing the risk of major bleeding or intracranial hemorrhage[4].

Hypersensitivity    reactions    (including    drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic edema) and  syncope were reported  in <1% of patients receiving ELIQUIS. This case is presented for the purpose of documentation  since it is an unusual occurrence in this medication.

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References

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  2. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke  and   thromboembolism   in atrial  fibrillation  using  a  novel  risk  factor- based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-72.
  1. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239-45.
  2. Sharma M, Cornelius VR, Patel JP, Davies JG, Molokhia M.  Efficacy and  Harms  of  Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism: Systematic Review and Meta-Analysis. Circulation. 2015;132(3):194-204.