Life-Threatening Non-Allergic Drug Hypersensitivity Reaction as a Very Rare Side Effect of Rivaroxaban Administration in the Netherlands

Abstract

Background:

Anticoagulant therapy is indicated for the prevention and treatment of thromboembolic disease. Direct oral anticoagulants (DOACs) are frequently prescribed and Rivaroxaban is the most frequently administered DOAC in the Netherlands. Most side effects relate to hemorrhagic complications, however, also non-hemorrhagic side effect may be potentially life threatening.

Case presentation:

A 74-year-old man presented at the emergency department with a ruptured infrarenal abdominal aortic aneurysm for which open aneurysm repair was performed. Postoperatively, the patient developed neurological deficit, respiratory and circulatory failure following rivaroxaban administration, initiated for atrial fibrillation. Even though, the clinical signs resembled an anaphylactic reaction, the skin-prick test was negative and complications most likely resulted from a non-allergic drug hypersensitivity reaction.

Conclusion:

This case report shows that non-allergic drug hypersensitivity reactions may mimic an anaphylactic reaction and can be potentially life threatening. In addition, severe non-hemorrhagic complications after rivaroxaban administration do occur and should be considered in case of acute clinical deterioration.

Introduction

There are various therapeutic options for the prevention and treatment of thromboembolic disease. The most frequently prescribed direct oral anticoagulant (DOAC) in the Netherlands is rivaroxaban (Xarelto©). ¹ In this case report we describe a very rare possible side effect of rivaroxaban and its potentially life-threatening presentation.

Case

A 74-year-old male presented with abdominal pain and a pulsating mass. Imaging showed a ruptured infrarenal abdominal aortic aneurysm unsuitable for endovascular repair. Open repair was performed using an infrarenal aortic graft. During intubation patient aspirated for which amoxicillin/clavulanic acid was started. Directly following surgery atrial fibrillation was diagnosed and low-molecular-weight heparin initiated (LMWH). Also, immediately postoperatively amlodipine was started for hypertension. Piritramide and fentanyl were initiated to reduce pain. The evening before discharge, 7 days after surgery, the LMWH was replaced by rivaroxaban.

Approximately, 8 hours after the first administration of rivaroxaban the patient started to shiver and experienced shortness of breath. Both signs were attributed to the previously diagnosed aspiration pneumonia. Thirteen hours after the initial dose, the patient suffered from reduced consciousness, tachycardia, decreased oxygen saturation levels (90%) and fever (38.9 °C). Physical examination showed swelling of the base of the tongue, pain in several joints and general muscle weakness; at that time he was unable to lift both his upper and lower limbs.

Laboratory testing showed elevated inflammatory markers and normal electrolytes (CRP 214 mg/L, Leukocytes 12.9 × 10⁹/L, sodium 136 mmol/L, potassium 3.4 mmol/L, glucose 5.7 mmol/L). Chest X-ray showed no abnormalities. The intensive care physician was alarmed and 2 possible diagnoses were considered: bacteremia and an allergic reaction to rivaroxaban. Given the severity of symptoms, clemastine 2 mg iv, hydrocortisone 100 mg iv and adrenaline 0.5 mg im were administered. The previously prescribed antibiotic was replaced by ceftriaxone and gentamycin. Rivaroxaban was withdrawn.

The patient developed generalized urticaria, and both the dyspnea and angioedema did not improve, therefore, the patient was admitted to the intensive care unit. Oxygen administration was sufficient to maintain adequate oxygen levels, intubation was not required. Because of a rapidly developing hypotension noradrenaline was initiated. After 2 days of maximal supportive care the symptoms gradually disappeared.

In an effort to clarify the underlying mechanism causing the acute respiratory, neurologic and circulatory failure additional laboratory and allergy testing was performed. Blood cultures taken during shivers and fever remained negative for microorganisms, C1 esterase inhibitor was normal (1.82 U/ml) and the inflammatory markers decreased. Additional, epi- and intracutaneous skin tests for rivaroxaban, amlodipine, piritramide and fentanyl were negative. Given the acute onset, the severity of symptoms and clinical presentation hours after rivaroxaban administration the response was attributed to a possible yet very rare side effect of rivaroxaban; a non-allergic drug hypersensitivity reaction.

Drug Hypersensitivity Reaction

Drug hypersensitivity reactions (DHRs) are pharmaceutical adverse effects that resemble allergic reactions and affect about 5% of the patient population.^2,3 DHRs can be an allergic or non-allergic (anaphylactoid) reaction. ⁴ Worldwide, drug hypersensitivity on rivaroxaban has been reported 171 times. ⁵ The non-allergic reaction, as described in this case report, has not been previously reported as a side effect of rivaroxaban in the Netherlands. ⁶

Rivaroxaban

Over recent decade, the use of DOACs has increased substantially in the Netherlands. In 2013, approximately 26,000 patients used a DOAC compared to over 202,000 patients in 2018. ⁷ With 113,140 registered patients in 2018, rivaroxaban is the most frequently used DOAC in the Netherlands. ⁷

Until April 2020 the Dutch Pharmacovigilance Centre Lareb received over 3100 reports of possible side effects regarding DOACs. 1290 (41%) reports were related to rivaroxaban, in total 2441 suspected side effects were reported. One or more serious suspected side effect was described in 40% of the reports. These suspected side effects have led to serious consequences such as hospitalization, life-threatening situations, lasting invalidity or death.

Allergic and Anaphylactic Reaction

The database on registered side effects of the World Health Organization (WHO) encounters over 22 million reports. ⁵ Of these, 145.473 relate to rivaroxaban. ⁵ Hypersensitivity has been reported 289 times. Severe allergic side effects such as anaphylactic reaction has been reported 49 times and anaphylactic shock is reported no more than 10 times. ⁵

In the Netherlands, until April 2020 Lareb received 1 report of anaphylactic reaction and no reports of anaphylactic shock related to rivaroxaban use. Allergic hypersensitivity was reported 5 times.

Discussion

Rivaroxaban is the most frequently prescribed DOAC in the Netherlands. ¹ Even though, most side effect are related to hemorrhagic complications, non-hemorrhage side effects do occur and may be potentially life threatening.

In our case, the clinical deterioration occurred hours after rivaroxaban administration and mimicked an anaphylactic reaction. A bacteremia was considered due to the fever and shivering. However, the blood cultures taken at that time were negative for micro-organism as was the additional imaging. The inflammatory markers decreased spontaneously, making an infectious origin very unlikely. The patient was referred to the allergist. The acute and broad spectrum of symptoms in relation to the previously started antibiotic treatment, for over 48 hours, made an anaphylactic reaction based on these agents implausable. Furthermore, the treatment with clemastine, hydrocortisone and adrenaline did not reduce the symptoms. The skin-prick test remained negative for rivaroxaban, amlodipine, piritramide and fentanyl. Thereby, making an IgE-mediated allergic reaction very unlikely.

After exclusion of an infectious origin and after testing for multiple drugs administered to the patient a non-allergic drug hypersensitivity reaction was considered. Anaphylaxis as presentation of a non-allergic drug hypersensitivity reaction typically occurs within hours after exposure.^8,9 Making rivaroxaban the most likely reason for the patients’ clinical deterioration.

Conclusion

In our case, we describe a very rare possible side effect of rivaroxaban resulting in neurological deficit, respiratory and circulatory failure. Although the clinical signs resembled an anaphylactic reaction, an allergy to rivaroxaban was ruled out by skin prick test and therefore most likely resulted from a severe non-allergic drug related hypersensitivity reaction to rivaroxaban.