Kahlon Navkirat, Doddi Sishir, Ning Ying, Akpunonu Basil, Murphy Julie
Hematology and Medical Oncology, College of Medicine and Life Sciences, The University of Toledo, Toledo, USA.
Medicine, College of Medicine and Life Sciences, The University of Toledo, Toledo, USA.
Cureus. 2022 Jun 13;14(6):e25907. doi: 10.7759/cureus.25907. eCollection 2022 Jun.
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.
根据一些观察性研究和体外研究，已知阿哌沙班会延长国际标准化比值（INR）。在因使用阿哌沙班导致INR升高的患者中，报告的INR中位数为1.4 - 1.7。阿哌沙班导致INR极度升高的情况罕见。对于接受血液透析（HD）的终末期肾病（ESRD）患者，尚无阿哌沙班使用的获批适应症；然而，有一些药代动力学数据支持在这类患者中使用该药。我们报告一例68岁的西班牙裔男性ESRD患者，其因INR为27.42而就诊于急诊室（ER）。INR检测是康复机构常规检查的一部分。查看用药清单，发现其包括每天两次服用2.5mg阿哌沙班，该药最近开始用于术后血栓预防。在急诊室重复进行INR检测以确认，结果报告为>18.5，凝血酶原时间>200秒。与五天前的基线检测相比，其肝功能检查结果稳定，胆红素正常，转氨酶略低于正常范围，有轻度低白蛋白血症。患者无任何活动性出血。阿哌沙班导致INR升高至>20是罕见事件。除直接口服抗凝剂（DOAC）外，未发现包括患者特征、实验室检查结果、并存疾病或其他药物等其他因素与INR升高有关。由于开始使用阿哌沙班前基线INR正常、肝功能检查结果稳定且停药后不久INR再次恢复正常，排除了肝硬化或维生素K缺乏作为INR升高原因。一项药代动力学研究发现，DOACs的血浆浓度与INR相关，这可能意味着该患者INR升高很可能是阿哌沙班血清浓度过高所致。然而，不建议通过监测INR来监测DOACs的抗凝活性。值得注意的是，肾脏清除占阿哌沙班清除的27%。药代动力学研究得出结论认为，半剂量阿哌沙班，即在血液透析患者中每天两次服用2.5mg（本病例使用的剂量），其药物暴露量与肾功能正常患者每天两次服用标准剂量5mg相似。未来有必要开展研究，以解决关于DOACs在ESRD患者中的安全性问题，进一步阐明与DOACs相关的此类高INR值的临床意义，并制定适当的管理指南。此后，安多凝血因子已被批准用于有危及生命出血的阿哌沙班逆转；然而，在没有出血证据的此类病例中不适用。
