Elevated International Normalized Ratio Due to Apixaban in Patient With End-Stage Renal Disease on Hemodialysis

Apixaban is known to prolong international normalized ratio (INR) per some observational and in vitro studies. In patients with elevated INR secondary to apixaban use, median INR of 1.4-1.7 has been reported. Extreme elevation in INR is rare with apixaban. In patients with end-stage renal disease (ESRD) on hemodialysis (HD), there are no labeled indications for apixaban use; however, there are some pharmacokinetic data supporting its use in such patients. We present a case of a 68-year-old Hispanic man with ESRD who presented to the emergency room (ER) with INR of 27.42. INR testing was done as a part of routine workup in rehabilitation facility. Medication list was reviewed and included apixaban 2.5 mg twice daily which was recently started for postoperative thromboprophylaxis. INR testing was repeated for confirmation in ER and was reported as >18.5 and prothrombin time >200 seconds. His liver function tests were stable as compared to baseline testing five days ago with normal bilirubin, low normal transaminases, and mild hypoalbuminemia. The patient didn’t have any active bleeding. An elevation of INR to >20 with apixaban is a rare event. No other factors including patient characteristics, laboratory results, co-existing conditions, or other medications except the direct oral anticoagulant (DOAC) were found to be responsible for elevated INR. Liver cirrhosis or vitamin K deficiency as cause for INR elevation was ruled out as the baseline INR was normal prior to starting apixaban, liver function tests were stable and INR normalized again shortly after discontinuing the medication. Plasma concentration of DOACs has been found to be correlating with the INR according to a pharmacokinetic study which potentially means that the high INR likely was secondary to high serum concentration of apixaban in this patient. However, INR monitoring is not recommended for monitoring anticoagulant activity of DOACs. As of note, renal clearance accounts for 27% of apixaban clearance. Pharmacokinetic studies have concluded that half dose apixaban, i.e., 2.5 mg twice daily in patients on hemodialysis (dose used in this case) results in drug exposure similar to that of the standard dose of 5 mg twice daily in patients with preserved renal function. Future studies are necessary to address questions about safety of DOACs in patients with ESRD, further elucidate the clinical significance of such high INR values associated with DOACs, and establish appropriate management guidelines. Andexanet alfa has since been approved for apixaban reversal in patients with life-threatening bleeding; however, would not be indicated in such cases when there is no evidence of bleeding.