Analysis of drugs inducing INR elevation by concomitant use of warfarin in inpatients

Objective To select drugs inducing international normalized ratio (INR) elevation by concomitant use of warfarin in inpatients. Methods The data of inpatients with increased INR rise (INR>3.50) because of concomitant use of warfarin and other drugs in Linyi People′s Hospital, Shandong University from January 2012 to December 2016 were collected and analyzed retrospectively. The baseline conditions, combination drugs, INR rise during treatments, bleeding events, treatments and outcomes in inpatients were recorded. Drugs that could increase anticoagulant effect of warfarin were screened. Results A total of 100 patients were enrolled in this study, including 43 men and 57 women aged from 26 to 86 years with an average age of (64±13) years. Primary diseases in 64 patients were atrial fibrillation, in 15 patients were after heart valve replacements, in 10 patients were pulmonary embolism, in 7 patients were lower extremity venous thrombosis, and in 4 patients were myocardial infarction with left ventricular thrombus. Hospital stay were 5-39 d and the average time was (17±7) d; the time of warfarin treatments were 3-36 d and the average time was (11±5) d. Of the 302 kinds of drugs combined with warfarin in the 100 patients, 40 kinds of drugs were found to induce INR elevation, including 16 kinds of anti-infective drugs (66 cases), 7 kinds of endocrine system drugs (28 cases), 4 kinds of cardiovascular system drugs (30 cases), 4 kinds of nervous system drugs (5 cases), 3 kinds of proton pump inhibitors (21 cases), 3 kinds of blood system drugs (4 cases), 2 kinds of proprietary Chinese medicine preparations (10 cases), 1 kind of non-steroidal anti-inflammatory drugs (2 cases). According to the number of drug use, the top ten drugs were piperacillin sodium and tazobactam sodium (27 cases), methylprednisolone (22 cases), levofloxacin (20 cases), amiodarone (20 cases), omeprazole (19 cases), cefoperazone sodium and sulbactam sodium (11 cases), fluvastatin sodium (10 cases), compound liquorice preparations (9 cases), voriconazole (7 cases), latamoxef (4 cases), and moxifloxacin (4 cases). The number of drug combination was 1-5 kinds in each patient, combination drug was 1 kind in 31 cases, 2 kinds in 46 cases, 3 kinds in 18 cases, 4 kinds in 4 cases, and 5 kinds in 1 case. Of the 100 patients with INR elevation, 83 patients stopped taking warfarin and 13 patients were given intramuscular injection of vitamin K1 at the same time, 17 patients′warfarin dose was decreased from 1.25-3.75 mg to 0.75-3.00 mg, then the INR levels in all patients decreased to <3.0. Seven patients had mild bleeding before warfarin withdrawal, including 4 cases of subcutaneous hemorrhage, 1 case of subarachnoid hemorrhage, 1 case of hematochezia, and 1 case of blood in phlegm. Conclusions Many commonly used drugs in clinical practice, such as compound preparations of β-lactam antibiotics and β-lactamase inhibitors, quinolones, glucocorticoid, anti-arrhythmic drugs, and proton pump inhibitors, etc., could cause INR elevation and increase bleeding risk. Key words: Warfarin; Drug interactions; International normalized ratio