Acute liver failure after changing oral anticoagulant from apixaban to rivaroxaban

Background

Rivaroxaban is a direct oral anticoagulant (DOAC) drug, used for treatment and prevention of deep venous and pulmonary thromboembolism.1 It is also commonly used to reduce the incidence of stroke in patients with atrial fibrillation. Randomised control trials have shown rivaroxaban to be non-inferior in efficacy and safety for the above indications when compared with the stalwart choice of warfarin.2 3 Though there is no significant difference in bleeding risk between the two, rivaroxaban can be administered without the need for ongoing laboratory and dose monitoring.1 3 This is due to its well understood pharmacological profile. It works by directly inhibiting factor Xa, an enzyme involved in the coagulation pathway. It is rapidly absorbed and has as a high bioavailability.4 Rivaroxaban has a dual elimination pathway, with approximately two-thirds of the drug being metabolised by hepatic cytochrome P450 enzymes; and the remaining one-third being eliminated unchanged in the urine.4

Bleeding is the most documented side-effect of rivaroxaban therapy. However, emerging postmarketing reports have increasingly shown an increased incidence of drug-induced liver injury (DILI) and acute liver failure (ALF). A 2018 systematic review reported 26 cases of acute or subacute liver damage due to rivaroxaban between the years 2006–2018, with a median time of onset of 15 days after initiation of the drug.5 In 2015, after 2 years of postmarketing surveillance of the US Food and Drug Administration Adverse Event Report System, 146 reports of DILI had been submitted for rivaroxaban, but only one had been submitted for apixaban.6 It appears that rivaroxaban is associated with a greater risk of DILI compared with apixaban; however, ongoing comparative postmarketing surveillance is needed to see whether this trend is preserved over a longer time-period.

Below, we present a case in which a patient developed ALF shortly following initiation of rivaroxaban, having previously tolerated apixaban without similar incident.

Case presentation

An 88-year-old man was initially admitted to hospital for a probable transient ischaemic attack (TIA) with acute-onset right arm and leg weakness. This was in the setting of subtherapeutically treated atrial fibrillation with apixaban and a 70% left carotid bulb stenosis, as demonstrated on a previous perfusion scan.

CT perfusion and angiography scans showed no evidence of acute ischaemic or haemorrhagic stroke. The patient’s limb weakness subsequently improved and his lower limb neurological examination was unremarkable. During this workup, it was established that the prescribed dose of apixaban of 2.5 mg two times per day, was likely subtherapeutic. The rationale for this dosing was unclear. Thus, the impression for the presentation was a possible TIA in the setting of inadequate anticoagulation. The patient also described a 7 kg weight loss in the preceding 4 months and was found to be anaemic with a haemoglobin of 84 g/L. A CT scan of the patient’s abdomen and pelvis demonstrated mild prominence of the gastro-oesophageal junction and suspected mural thickening of the rectum. A gastroscopy found moderate gastritis and oesophagitis, but no active bleeding was identified. A haemolytic screen was negative. The patient’s anticoagulant was then changed to 15 mg of rivaroxaban daily, although the reason for this change as well as the use of an adjusted dose is unclear on review of documentation. The patient was discharged 8 days later with a plan for an outpatient colonoscopy. At the time of discharge, the patient’s transaminases were normal (alanine aminotransferase (ALT) 23 U/L, GGT 46 U/L, alkaline phosphatase (ALP) 307 U/L, bilirubin 28 μmol/L, international normalised ratio (INR) 1.9, Ferritin 740 μg/L) he was not thrombocytopenic (161×10⁹/L) and had stable kidney function (estimated glomerular filtration rate 70–80 mL/min, creatinine 80–90 mcmol/L). He continued his usual medications of atorvastatin and verapamil, which were both longstanding.

Two weeks later, the patient represented with nausea, vomiting and worsening lethargy. These symptoms had progressively worsened over the course of the week leading up to his presentation. He was afebrile and haemodynamically stable on presentation. He was jaundiced but without evidence of hepatic flap or confusion.

Investigations

Laboratory investigation revealed a significant mixed hyperbilirubinaemia (total bilirubin 1903 μmol/L, unconjugated 115 bilirubin μmol/L/L), transaminase rise (ALT 1940 U/L, AST 2304 U/L, ALP 360 U/L), elevated ferritin (26 218 μg/L) as well as thrombocytopenia and significantly elevated INR of 14 and APTT of 57. A rivaroxaban level taken on admission was found to be 117.1 ng/mL. An admission COVID-19 swab was found to be negative. The patient was once again found to be anaemic, with a haemoglobin of 67 g/L. Again, there was no evidence of acute bleeding. On further questioning, there was no prior history of chronic liver disease, alcohol abuse or illicit drug abuse. Blood alcohol, paracetamol levels and viral hepatitis serology panel were negative. Screening for autoimmune liver disease was also negative. A liver ultrasound showed moderate hepatic steatosis, which was also noted on his prior CT abdomen, with no evidence of cirrhosis or portal hypertension and no focal liver lesions.

Treatment

All the patient’s medications were with held, and he was treated with vitamin K, multiple units of fresh frozen plasma and packed red blood cells. The patient was also given an n-acetylcysteine infusion based on previous study findings showing a mortality benefit and reduced hospital stay when used in non-paracetamol DILI.7

Outcome and follow-up

By day 2, the patient’s liver enzymes began to downtrend, his INR reduced to 1.4, APTT improved to 38 and his haemoglobin incremented to 116 g/L. He also reported feeling symptomatically improved. As illustrated in figures 1 and 2, there was a downward trend in liver enzymes and bilirubin over the following week (1-week postrivaroxaban cessation: ALT 397 U/L, total bilirubin 82 μmol/L, AST 142 U/L, ALP 282 U/L, ferritin 3470 μg/L).

Figure 1

Trend in liver function tests during patient admission. rivaroxaban likely ceased 1–2 days prior and definitively ceased on admission. there was no previous aspartate level prior to this admission, ALT on commencement of rivaroxaban was 23 U/L

Figure 2

Trend in total bilirubin during patient admission. rivaroxaban likely ceased 1–2 days prior and definitively ceased on admission.

Despite the resolution of the patient’s ALF, he had an ongoing thrombocytopenia and a progressive anaemia. A repeat haemolytic screen was negative (haptoglobin 0.9, nil urinary haemosiderin, retics 1.5, DAT negative). A blood film during his admission showed a leucoerythroblastic shift. A bone marrow aspirate demonstrated markedly fibrotic marrow with distorted architecture as well as a marked increase in distorted megakaryocytes. In addition, his aforementioned CT abdomen demonstrated an enlarged spleen of 12.2 cm. Finally, he was found to have a positive JAK2 mutation in V617F. Thus, the patient was given an additional diagnosis of primary myelofibrosis. In retrospect, this diagnosis may have contributed to the patient’s initial TIA presentation, despite being anticoagulated. In terms of anticoagulation for his atrial fibrillation, the patient was discharged on long-term low-dose enoxaparin rather than reverting to apixaban.