Background: Amiodarone and warfarin are sometimes administered immediately after cardiac surgery. Although the interaction between long-term oral amiodarone and warfarin has been reported, the interaction between warfarin and short-term intravenous amiodarone has not been reported. In this study, we investigated the effect of short-term intravenous amiodarone on the anticoagulant effect of warfarin in patients who underwent cardiac surgery. Methods: We retrospectively reviewed the medical records of 11 patients who received oral warfarin before and after cardiac surgery, and loading doses of 125–150 mg or a 750 mg continuous infusion of amiodarone, or both in the intensive care unit (ICU) within 5 days after the surgery between July 2011 and January 2017. The prothrombin time-international normalized ratio (PT-INR)/daily warfarin dose (PT-INR/dose) was used as an indicator of anticoagulant effect. The values before surgery were considered as the baseline. Results: The PT-INR and PT-INR/dose values were elevated in 7 and 10 patients, respectively, after amiodarone administration. The mean PT-INR values were not significantly different before and after amiodarone administration (2.13 ± 0.58 vs 2.29 ± 0.50, respectively, p = 0.643). In contrast, the mean PT-INR/dose values were significantly elevated after the administration of amiodarone (0.93 ± 0.46 vs 1.54 ± 0.63, respectively, p = 0.002). Conclusions: Short-term intravenous amiodarone enhanced the anticoagulant effect of warfarin in patients admitted to the ICU after cardiac surgery. We suggest that the dose of warfarin should be carefully adjusted for a few days after cardiac surgery if intravenous amiodarone is coadministered. Keywords: Warfarin, Amiodarone, Interaction, Intravenous, Prothrombin time, Cardiac surgery, Intensive care unit, Short-term Background complicated by multiple factors including unstable pa- Warfarin is an essential drug for the prevention of tient condition and concomitant use of various medica- thrombosis after valvular surgery, which has a narrow tion [4, 5]. Moreover, the altered pharmacokinetic therapeutic range. Although there are general dosing parameters reported in these critical patients compared guidelines, the dosing of warfarin is complicated by rela- with those who are non-critically ill contributes to the tively high incidences of drug-drug interactions and challenge of controlling the warfarin dose . inter-patient variability [1–3]. Controlling the dosage of Postoperative atrial fibrillation after cardiac surgeries warfarin in patients admitted to the intensive care unit has been reported in approximately 30% of cases, and (ICU) immediately after cardiac surgery can be especially short-term intravenous amiodarone is sometimes neces- sary for treatment . Amiodarone is known to induce drug-drug interactions with warfarin that could lead to * Correspondence: email@example.com excessive anticoagulation and bleeding risk [8–12]. Simi- Department of Pharmacy, Kobe City Medical Center General Hospital, 2-2-1, Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan lar to warfarin, amiodarone is metabolized in the liver by Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Takase et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:13 Page 2 of 6 the drug-metabolizing enzyme cytochrome P450 (CYP), In the both study groups, all patients received cefazo- which it inhibits. The mechanism of the drug-drug inter- lin for 3 days followed by surgery for the prevention of action between warfarin and amiodarone is due to the surgical site infection. The PT-INR values were fre- inhibition of CYP. Amiodarone and its active metabolite quently monitored during the study period, especially “desethylamiodarone” inhibit CYP2C9, which increases after the patients were admitted to the ICU. The daily the anticoagulation effect of warfarin . doses of warfarin were adjusted as necessary to maintain Amiodarone has unique pharmacokinetic properties, a therapeutic PT-INR of 1.5–2.0, which is suitable for and following oral administration, it is approximately Japanese patients [17, 18]. The PT-INR/daily dose of 40% bioavailable and 96% plasma protein bound. The warfarin (PT-INR/dose) was used as an indicator of the mean half-life of amiodarone is 40–55 days [13–15]. anticoagulant effect . In this study, PT-INR/dose was Therefore, it may require 130–535 days (five half-lives) calculated as follows: for amiodarone to reach steady-state levels. To date, various studies have reported drug-drug interactions PT‐INR=dose ¼ PT‐INR=dose of warfarin of the previous day: between warfarin and long-term oral amiodarone ad- ministration [8–12]. However, little is known about the interactions between warfarin and intravenous amioda- Before the surgery, the daily doses of warfarin, PT-INR rone . To our knowledge, there have not been any value, and PT-INR/dose ratio were stable in the study previously reported on the drug-drug interaction be- subjects and were considered as the baseline values. tween warfarin and short-term intravenous amiodarone in an ICU setting. Thus, we investigated the effect of Statistical analysis short-term intravenous amiodarone on the anticoagulant All data are expressed as the mean ± standard deviation. effect of warfarin in patients who underwent cardiac Statistical analyses were performed using the JMP Pro surgery. 12.2.0 (SAS Institute Inc., Cary, NC, USA). To compare categorical data, the Chi-square test was used. For con- Methods tinuous data, values were presented as mean ± standard This retrospective study protocol was approved by the in- deviation (SD). Student’s t-test was used to compare stitutional review board of the Kobe City Medical Center groups. The changes in PT-INR and PT-INR/dose were General Hospital, Japan (Approval No. zn170806). Patient analyzed using a paired t-test. All p-values < 0.05 were characteristics including age, sex, indications for receiving considered statistically significant. warfarin and amiodarone, the dose of warfarin and amio- darone, prothrombin time-international normalized ratio Results (PT-INR), and underlying organic heart diseases were The patient characteristics are shown in Table 1. Valvular reviewed using the electronic medical record system. heart disease was the most common cardiovascular co- Patients who received oral warfarin before and after car- morbidity. In the baseline value, dosage of warfarin and diac surgery, as well as loading doses of 125 to 150 mg or PT-INR value were not significantly different in the both subsequent continuous infusion of 750 mg amiodarone or groups. Except for cefazoline, there was no change in com- both in the ICU within 5 days after surgery between bination of drugs known to influence pharmacokinetics July 1, 2011, and January 31, 2017 were selected as the and pharmacodynamics of warfarin. amiodarone group (n = 11). Consecutive 15 patients who received oral warfarin before and after cardiac sur- Changes in mean PT-INR values and PT-INR/dose gery without amiodarone between May 1, 2016, and Janu- Changes in the PT-INR values and dosages of warfarin ary 31, 2017 were selected as the control group (n =15). in all patients before and after the amiodarone injection Patients were excluded from both study groups if they are shown in Fig. 1. Compared with baseline values, received oral amiodarone or other drugs (fluconazole, mi- those of the PT-INR were increased in seven patients conazole, bucolome, benzbromarone, rifampicin) known (63.6%) (cases 2, 3, 6, 7, 8, 10 and 11) after the adminis- to markedly alter the effect of warfarin during the study tration of amiodarone. Except for one patient (case 8), period . In the amiodarone group, among 307 patients the time points which the daily warfarin doses were admitted to the ICU and received intravenous amioda- reduced after amiodarone injection were observed. rone, 25 patients have received warfarin before cardiac The change in PT-INR/dose values of all patients is surgery. Fourteen patients were excluded because they re- shown in Fig. 2. The PT-INR/dose ratio increased in 10 ceived oral amiodarone (n = 8), or bucolome (n =1) or patients (90.9%) (cases 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11) other medication (n = 5). Residual 11 patients met the after administration of amiodarone. Although the me- inclusion criteria and were followed up for 15 days after dian time to reach the peak value of PT-INR/dose was the initial dose of intravenous amiodarone. 5 days after amiodarone injection, the values were not Takase et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:13 Page 3 of 6 Table 1 Patient characteristics consistent in each case. Summarized data in the amioda- rone group are shown in Table 2. Amiodarone Control p-values (n = 11) (n = 15) The mean PT-INR values were not significantly different Age, years (mean ± SD) 67.2 ± 7.5 71.7 ± 6.5 0.100 before and after surgery in the control group (2.27 ± 0.58 vs 2.25 ± 0.47, respectively, p = 0.912, Fig. 3a)and ami- Men/Women, n 4/7 6/9 0.851 odarone group (2.13 ± 0.58 vs 2.29 ± 0.50, respectively, Cardiovascular comorbidity, n – p = 0.643, Fig. 3a). Valvular heart disease 8 13 Although the mean PT-INR/dose values were not Ischemic heart disease 1 0 significantly elevated after surgery compared with the Thoracic aortic aneurysm 1 0 baseline value in the control group (0.86 ± 0.36 vs Aortic dissection 0 1 1.11 ± 0.56, respectively, p = 0.108, Fig. 3b), those values were significantly elevated compared with the Aortic dissection + Ischemic 10 heart disease baseline value in the amiodarone group (0.92 ± 0.45 vs Valvular heart disease + Ischemic01 1.54 ± 0.62 respectively, p = 0.002, Fig. 3b). heart disease Warfarin indication (preoperative), n – Discussion In this study, we investigated the effect of short-term Atrial fibrillation 4 11 intravenous amiodarone on the anticoagulant effect of Post prosthetic valve replacement 4 4 warfarin in patients admitted to the ICU after cardiac Low LVEF 3 0 surgery. The result showed that in most patients, the Dosage of warfarin (baseline), 2.64 ± 0.89 3.07 ± 1.22 0.370 dosage of warfarin was reduced and the PT-INR, as well mg/day (mean ± SD) as the PT-INR/dose, were elevated after the administra- PT-INR value (baseline) (mean ± SD) 2.13 ± 0.58 2.27 ± 0.58 0.551 tion of amiodarone compared with baseline values. The LVEF left ventricular ejection fraction PT-INR values were carefully monitored, and warfarin dosages were frequently adjusted, and the maximal Fig. 1 Change in values of prothrombin time-international normalized ratio (PT-INR, solid line, left line) and warfarin dosage (gray area, right axis) in the amiodarone group. X-axis shows days after administration of amiodarone Takase et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:13 Page 4 of 6 Fig. 2 Change in prothrombin time-international normalized ratio/daily warfarin dose (PT-INR/dose) values (solid line) in the amiodarone group. X-axis shows days after administration of amiodarone PT-INR values were not different from the baseline co-treatment was started [9–12]. On the other hand, values both in the control and amiodarone groups. In Edwin et al.  evaluated drug-drug interactions in pa- contrast, the mean maximal PT-INR/dose values after tients who were coadministered amiodarone and warfarin intravenous amiodarone treatment were significantly and were admitted to the hospital . They reported that elevated only in the amiodarone group compared to the the rate of PT-INR values > 2 observed 4 days after the baseline, and the timing of elevation was not consistent initiation of warfarin treatment was higher in the group between cases. coadministered warfarin and amiodarone than in the Previous studies reported that co-administration of war- group treated with warfarin alone . Although they farin and amiodarone increased the bleeding risk by en- reported short-term amiodarone treatment, they only hancing the anticoagulant effect of warfarin [9–12, 20, 21]. included patients who received both drugs for at least 4– In out-patients who received both warfarin and amioda- 5 days. In addition, the mean amiodarone dose in that rone long-term, the drug-drug interaction induced by study was approximately 1000 mg/day, which was higher their co-administration was observed several weeks after than those in our study. We focused on the effect of amiodarone injections administered for 1–3 day only on Table 2 Time to reach the peak values and change in values the anticoagulant effect of warfarin in patients admitted to after amiodarone injection in the amiodarone group (n = 11) the ICU after cardiac surgery. The result showed that the Median (range) anticoagulant effect was increased by amiodarone, even Time to reach the peak values (days) following this short-term treatment. PT-INR 5 (2–14) After cardiac surgery, some drugs added after surgery. However, we excluded patients who received medica- PT-INR / Dose of warfarin 5 (2–14) tions which can strongly influence pharmacokinetics and Change in values from baseline to the maximal value pharmacodynamics of warfarin . Cefazolin is known PT-INR 0.36 (−1.61–1.19) to influence the effect of warfarin, it was administered PT-INR / Dose of warfarin 0.60 (−0.23–1.62) for all patients in the amiodarone and control group. Takase et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:13 Page 5 of 6 ab Fig. 3 Changes in a prothrombin time-international normalized ratio (PT-INR) and b PT-INR/daily warfarin dose (PT-INR/dose) before and after surgery in the control (n = 15) and the amiodarone (n = 11) groups. The latter represents maximal value during study period. The bold lines represent the median values Except for cefazoline, there was no change in combin- make it more difficult to control the anticoagulation sta- ation of drugs known to influence pharmacokinetics and tus . This study is useful because it partially explains pharmacodynamics of warfarin. Therefore, we believe the observed variation in the PT-INR. the increase in PT-INR/dose was affected by amioda- This study has some limitations. First, it appears that rone. Warfarin is a racemic mixture, and the anticoagu- not only amiodarone injection, but also cardiac surgery lant effect of (S)-warfarin is 5-folds stronger than that of can affect the anticoagulant effect of warfarin. Previous (R)-warfarin is. The (S)- and (R)-warfarin enantiomers studies have suggested that the PT-INR values in pa- are metabolized by the drug-metabolizing CYP2C9 and tients who underwent cardiac surgeries were increased CYP3A4 enzymes, respectively . In this study, we con- after surgery compared with the values before surgery sidered that the inhibition of CYP2C9 by amiodarone . In our study, although the values of PT-INR/dose and its active metabolite desethylamiodarone increased were not significantly different between before and after the anticoagulant effect of warfarin. Frequent dose ad- surgery without administration of amiodarone, the status justment of warfarin appeared to maintain the PT-INR after cardiac surgery individually can be different. In fact, values within the therapeutic range, and no significant the values of PT-INR/dose were not increased in some difference occurred in the PT-INR values between base- patients. We speculate that genetic polymorphisms of line and after administration of amiodarone. In contrast, CYP2C9 and/or difference of volume of distribution in the PT-INR/dose values were elevated after administra- each individual may affect the degree of this dug-drug tion of amiodarone in most patients. We considered that interaction. the administration of amiodarone could elevate the Second, not all the PT-INR values were measured PT-INR/dose. In addition, the median time to achieve during the study period. During the 7.5-day mean ICU the peak value of the PT-INR/dose was 5 days after stay of these patients, they were closely monitored to amiodarone injection. This time lag between the amio- minimize bleeding. However, after the patients were darone injection and the peak time of the PT-INR/dose moved to general wards, the PT-INR was not monitored can be explained by the large volume of distribution and daily. Finally, the study retrospectively evaluated a small the long half-life of amiodarone [13, 14]. Although the sample size. To overcome these limitations, further re- PT-INR values were monitored daily, in patients admit- search is needed to compare the PT-INR values between ted to the ICU after cardiac surgery, complex pharmaco- patients receiving warfarin with or without short-term therapy with multiple medications make it difficult to amiodarone treatment in larger sample sizes. control the PT-INR values within an adequate range. In addition, the decrease in coagulation factors by surgical Conclusions invasion with cardiopulmonary bypass and the dilution To the best of our knowledge, this is the first study to following the administration of crystalloids could also show that short-term administration of intravenous Takase et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:13 Page 6 of 6 amiodarone enhanced the anticoagulant effect of warfarin 8. Lu Y, Won KA, Nelson BJ, et al. Characteristics of the amiodarone- warfarin interaction during long-term follow-up. 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Prediction of pharmacokinetic drug- TT, HI, and MT conceived and designed this study. TT, HI, and MT collected drug interaction caused by changes in cytochrome P450 activity using in and analyzed data. HU, HM, TK and TH supervised the conduct of this study. vivo information. Pharmacol Ther. 2010;125:230–48. TT and IH drafted the manuscript, and all authors contributed substantially to 17. Liu T, Hui J, Hou YY, et al. Meta-analysis of efficacy and safety of low- its revision. All authors read and approved the final manuscript. intensity warfarin therapy for east asian patients with nonvalvular atrial fibrillation. Am J Cardiol. 2017;120:1562–7. 18. Kodani E, Atarashi H, Inoue H, et al. Target intensity of anticoagulation with Ethics approval and consent to participate warfarin in Japanese patients with valvular atrial fibrillation – subanalysis of This study was approved by the Institutional Review Board of Kobe City the J-RHYTHM registry. Circ J. 2015;79:325–30. Medical Center General Hospital and the Board waived the need for patients’ 19. Halkin H, Shapiro J, Kurnik D, et al. Increased warfarin doses and decreased consent (No. zn170806). international normalized ratio response after nationwide generic switching. Clin Pharmacol Ther. 2003;74:215–21. Competing interests 20. Holm J, Lindh JD, Andersson ML, et al. The effect of amiodarone on The authors declare that they have no competing interests. warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost. 2017;15:446–53. 21. Santos PC, Soares RA, Strunz CM, et al. Simultaneous use of amiodarone Publisher’sNote influences warfarin maintenance dose but is not associated with adverse Springer Nature remains neutral with regard to jurisdictional claims in events. J Manag Care Spec Pharm. 2014;20:376–81. published maps and institutional affiliations. 22. SelimovićČeke L, Imamović S, Ljuca F, et al. 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