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Aims: Genotype‐guided dosing algorithms can explain about half of the interindividual variability in prothrombin time–international normalized ratio (PT‐INR) under warfarin treatment. This study aimed to refine a published kinetic–pharmacodynamic model and guide warfarin dosage for an optimal PT‐INR based on renal function. Methods: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT‐INR measurements, we refined the kinetic–pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear‐mixed‐effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT‐INR (2.0–3.0 or 1.6–2.6) based on the significant covariates. Results: A total of 350 patients with 2762 PT‐INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6–199.0] mL/min/1.73 m2). The final kinetic–pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT‐INR range as eGFR decreased. Conclusions: Model‐informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment. [ABSTRACT FROM AUTHOR]

Objectives: To investigate factors influencing postoperative bleeding occurrence after dental extraction in older patients receiving anticoagulation therapy. Materials and methods: This retrospective study included patients aged ≥ 65 years receiving one of the following anticoagulants: apixaban, edoxaban, rivaroxaban, and warfarin. Patients who underwent one to multiple tooth extractions in the geriatric dentistry clinic at Tokyo Medical and Dental University Hospital between August 1, 2016, and November 30, 2020, were included. The outcome variable was postoperative bleeding occurrence. Logistic regression analysis was performed with the following ten factors as explanatory variables: age, sex, maximum systolic blood pressure during the extraction, type of local anesthesia, vertical incision, osteotomy, usage of surgical splints, the mesiodistal width of the extracted tooth on a radiograph, use of antiplatelet agents, and history of diabetes requiring medication. Results: Among 395 participants (mean age, 82.3 ± 6.5 years) included in this study, 75 patients experienced postoperative bleeding after tooth extraction. Logistic regression analysis revealed that the odds ratios for the vertical incision (18.400, p < 0.001), osteotomy (3.630, p = 0.00558), usage of surgical splints (1.860, p = 0.0395), and the mesiodistal width of the extracted tooth on a radiograph (1.060, p = 0.0261) were statistically significant. Conclusions: For dental extraction in older patients receiving anticoagulants, postoperative bleeding is more likely to occur in patients with vertical incision, osteotomy, and posterior or multiple tooth extractions. Clinical relevance: Dentists should consider suturing and adjunctive hemostatic procedures for patients undergoing vertical incision, osteotomy, and multiple tooth extractions while receiving anticoagulation therapy to minimize the risk of postoperative bleeding. [ABSTRACT FROM AUTHOR]

Apixaban is a direct oral anticoagulation agent that exerts its effect through the direct inhibition of factor Xa. We treated a case of massive intoxication with 70 tablets of apixaban and have presented the clinical course of the associated anti-Xa activities. A 49-year-old woman was admitted to the emergency department approximately 1.5 h after impulsive self-intoxication with 175 mg of apixaban. She developed coagulopathy with prothrombin time-international normalized ratio (PT-INR) of 3.65, activated partial thromboplastin time of 56.5 s, and antithrombin activity (AT) of >150% (at 1.5 h post-ingestion). The patient’s initial and peak anti-Xa activity was 17.7 IU/mL, and its elimination displayed first-order kinetics with a half-life of 10.5 h. The patient’s anti-Xa activity was within the therapeutic dose range at 26 h post-ingestion, and she recovered without experiencing any bleeding complications. Her coagulopathy also returned to normal level at the same timing. This result suggests that PT-INR and AT can be used as substitute markers of overwhelmed anticoagulation following massive overdose of apixaban. A case of apixaban overdose with associated anti-Xa activities was presented. There was favorable resolution of anticoagulation without specific treatments.

Abstract Background The study aimed to assess the correlation between the monitoring frequency of PT-INR and the long-term prognosis in patients with mechanical heart valve (MHV) replacement after discharge. Methods This single-center, observational study enrolled patients who underwent MHV replacement and discharged from June 2015 to May 2018. Patients or their corresponding family members were followed with a telephone questionnaire survey in July-October 2020. Based on monitoring intervals, patients were divided into frequent monitoring (FM) group (≤ 1 month) and less frequent monitoring (LFM) group (> 1 month). The primary endpoint was the composite of thromboembolic event, major bleeding or all-cause death. The secondary endpoints were thromboembolic event, major bleeding or all-cause death, respectively. Results A total of 188 patients were included in the final analysis. The median follow-up duration was 3.6 years (Interquartile range: 2.6 to 4.4 years). 104 (55.3%) patients and 84 (44.7%) patients were classified into the FM group and the LFM group, respectively. The FM group had a significantly lower incidence of the primary endpoint than the LFM group (3.74 vs. 1.16 per 100 patient-years, adjusted HR: 3.31 [95% CI 1.05–10.42, P = 0.041]). Secondary analysis revealed that the risk of thromboembolic events and all-cause death were also reduced in the FM group. Conclusions The management of warfarin treatment in patients after MHV replacement remains challenging. Patients with less frequent monitoring of PT-INR might have worse clinical prognosis than those with frequent PT-INR monitoring.

Background: The study aimed to assess the correlation between the monitoring frequency of PT-INR and the long-term prognosis in patients with mechanical heart valve (MHV) replacement after discharge. Methods: This single-center, observational study enrolled patients who underwent MHV replacement and discharged from June 2015 to May 2018. Patients or their corresponding family members were followed with a telephone questionnaire survey in July-October 2020. Based on monitoring intervals, patients were divided into frequent monitoring (FM) group (≤ 1 month) and less frequent monitoring (LFM) group (> 1 month). The primary endpoint was the composite of thromboembolic event, major bleeding or all-cause death. The secondary endpoints were thromboembolic event, major bleeding or all-cause death, respectively. Results: A total of 188 patients were included in the final analysis. The median follow-up duration was 3.6 years (Interquartile range: 2.6 to 4.4 years). 104 (55.3%) patients and 84 (44.7%) patients were classified into the FM group and the LFM group, respectively. The FM group had a significantly lower incidence of the primary endpoint than the LFM group (3.74 vs. 1.16 per 100 patient-years, adjusted HR: 3.31 [95% CI 1.05–10.42, P = 0.041]). Secondary analysis revealed that the risk of thromboembolic events and all-cause death were also reduced in the FM group. Conclusions: The management of warfarin treatment in patients after MHV replacement remains challenging. Patients with less frequent monitoring of PT-INR might have worse clinical prognosis than those with frequent PT-INR monitoring. [ABSTRACT FROM AUTHOR]

Abstract Background The standard anticoagulation therapy for patients implanted with left ventricular assist devices (LVADs) includes warfarin therapy. We developed a cloud-based home medical management information-sharing system named as LVAD@home. The LVAD@home system is an application designed to be used on iPad tablet computers. This system enables the sharing of daily information between a patient and care providers in real time. In this study, we reported cases of outpatients with LVADs using this system to manage anticoagulation therapy. Case presentation The patient, a man in his 40s with end-stage heart failure owing to non-ischemic dilated cardiomyopathy, underwent LVAD implantation and warfarin was started on postoperative day 1. He started to use LVAD@home to manage warfarin therapy after discharge (postoperative day 47). He sent his data to care providers daily. By using this system, the pharmacist observed his signs of reduced dietary intake 179 days after discharge, and after consulting the physician, told the patient to change the timing of the next measurement earlier than usual. On the next day, the prothrombin time-international normalized ratio increased from 2.0 to 3.0, and thus the dose was decreased by 0.5 mg. Four patients used this system to monitor warfarin therapy from October 2015 to March 2018. In these patients, the time in therapeutic range was 90.1 ± 1.3, which was higher than that observed in previous studies. Additionally, there were no thromboembolic events or bleeding events. Conclusions The cloud-based home management system can be applied to share real-time patient information of factors, including dietary intake that interact with warfarin. It can help to improve long-term anticoagulation outcomes in patients implanted with LVAD.

Abstract Background Although recombinant human soluble thrombomodulin (rTM) has been widely used to treat disseminated intravascular coagulation (DIC) in Japan, there is no consensus regarding rTM efficacy. Therefore, if the factors influencing rTM efficacy is revealed, it may be possible to demonstrate the effectiveness of rTM by limiting the patients who use rTM. This study investigated the factors of rTM treatment which influence DIC status. Methods This retrospective case-control study enrolled hospitalized adult patients treated with rTM from October 2010 to May 2020. Among these patients, 227 who were diagnosed with DIC according to the Japanese Association for Acute Medicine DIC scoring system were assessed. The primary endpoint was the 28-day mortality after rTM treatment. For Cox-proportional hazards model, explanatory factors determined using univariate analysis with p

Background: The 2018 Osaka earthquake caused severe damage to the National Cerebral and Cardiovascular Center, and the interruption to the delivery of hospital food in particular had a significant effect on patients with left ventricular assist devices (LVAD). Methods and Results: We retrospectively assessed 10 patients who had been provided with emergency rations on the day of earthquake and the next day for breakfast. Catered foods were provided thereafter. Vitamin K content was largely reduced due to emergency rations; the prothrombin time-international normalized ratio (PT-INR) on day 2 was significantly higher than on day 1. Conclusions: Close monitoring of PT-INR and assessing vitamin K content may be important for preventing complications in patients with a LVAD during a disaster., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Objective: To evaluate the prognostic value of routine coagulation tests for patients with heat stroke.Methods: This was a multi-center retrospective study. Patients who arrived at the hospital <24 h after the onset of Heat Stroke (HS) were included. The routine coagulation variables were detected within 24 h after the onset, including the lowest platelet count (PLC).Results: 60-day mortality rate was 20.9%. The median Prothrombin Time-International Normalized Ratio (PT-INR) of the non-surviving patients was significantly higher than that of the survivors (P < 0.01). The median Activated Partial Thromboplastin Time (APTT) in non-surviving patients was significantly higher than in the surviving patients (P < 0.01). A Cox regression analysis revealed that 60-day mortality was associated with PT-INR (P = 0.032) and APTT (P = 0.004). The optimal PT-INR point for predicting 60-day mortality rate was 1.7. The optimal APTT point for predicting 60-day mortality was 51.45. Patients with increased PT-INR (≥1.7) levels had, overall, a significantly reduced survival time (P < 0.01). Patients with elevated APTT (≥51.45) also had a decrease in survival time (P < 0.01). The prognostic scoring, with increased PT-INR (≥1.7) and prolonged APTT (≥51.45) at one point each, was also demonstrated to be useful in predicting 60-day mortality. Patients whose temperature fell to 38.9 °C within 30 min had significantly lower levels of PT-INR and APTT within 24 h than those who took longer to cool down.Conclusions: A prolonged APTT and elevated PT-INR within 24 h are independent prognostic factors of 60-day mortality in HS. [ABSTRACT FROM AUTHOR]

Background: The standard anticoagulation therapy for patients implanted with left ventricular assist devices (LVADs) includes warfarin therapy. We developed a cloud-based home medical management information-sharing system named as LVAD@home. The LVAD@home system is an application designed to be used on iPad tablet computers. This system enables the sharing of daily information between a patient and care providers in real time. In this study, we reported cases of outpatients with LVADs using this system to manage anticoagulation therapy. Case presentation: The patient, a man in his 40s with end-stage heart failure owing to non-ischemic dilated cardiomyopathy, underwent LVAD implantation and warfarin was started on postoperative day 1. He started to use LVAD@home to manage warfarin therapy after discharge (postoperative day 47). He sent his data to care providers daily. By using this system, the pharmacist observed his signs of reduced dietary intake 179 days after discharge, and after consulting the physician, told the patient to change the timing of the next measurement earlier than usual. On the next day, the prothrombin time-international normalized ratio increased from 2.0 to 3.0, and thus the dose was decreased by 0.5 mg. Four patients used this system to monitor warfarin therapy from October 2015 to March 2018. In these patients, the time in therapeutic range was 90.1 ± 1.3, which was higher than that observed in previous studies. Additionally, there were no thromboembolic events or bleeding events. Conclusions: The cloud-based home management system can be applied to share real-time patient information of factors, including dietary intake that interact with warfarin. It can help to improve long-term anticoagulation outcomes in patients implanted with LVAD. [ABSTRACT FROM AUTHOR]

What is known and objective: Vitamin K deficiency is known to cause impaired coagulation. We report a case of marked prolongation of the prothrombin time‐international normalized ratio (PT‐INR) associated with warfarin and vitamin K deficiency caused by endoscopic nasobiliary drainage (ENBD). Case presentation: Oral administration of warfarin was initiated in a 67‐year‐old man after left hemihepatectomy. He developed a biliary fistula after surgery that was treated by ENBD, which resulted in significant prolongation of the PT‐INR. What is new and conclusion: The effect of warfarin was enhanced in this patient due to reduced absorption of vitamin K as a result of external biliary drainage. [ABSTRACT FROM AUTHOR]

Objectives: To investigate factors influencing postoperative bleeding occurrence after dental extraction in older patients receiving anticoagulation therapy., Materials and Methods: This retrospective study included patients aged ≥ 65 years receiving one of the following anticoagulants: apixaban, edoxaban, rivaroxaban, and warfarin. Patients who underwent one to multiple tooth extractions in the geriatric dentistry clinic at Tokyo Medical and Dental University Hospital between August 1, 2016, and November 30, 2020, were included. The outcome variable was postoperative bleeding occurrence. Logistic regression analysis was performed with the following ten factors as explanatory variables: age, sex, maximum systolic blood pressure during the extraction, type of local anesthesia, vertical incision, osteotomy, usage of surgical splints, the mesiodistal width of the extracted tooth on a radiograph, use of antiplatelet agents, and history of diabetes requiring medication., Results: Among 395 participants (mean age, 82.3 ± 6.5 years) included in this study, 75 patients experienced postoperative bleeding after tooth extraction. Logistic regression analysis revealed that the odds ratios for the vertical incision (18.400, p < 0.001), osteotomy (3.630, p = 0.00558), usage of surgical splints (1.860, p = 0.0395), and the mesiodistal width of the extracted tooth on a radiograph (1.060, p = 0.0261) were statistically significant., Conclusions: For dental extraction in older patients receiving anticoagulants, postoperative bleeding is more likely to occur in patients with vertical incision, osteotomy, and posterior or multiple tooth extractions., Clinical Relevance: Dentists should consider suturing and adjunctive hemostatic procedures for patients undergoing vertical incision, osteotomy, and multiple tooth extractions while receiving anticoagulation therapy to minimize the risk of postoperative bleeding., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Glottic insufficiency negatively affects phonation and swallowing function. Injection laryngoplasty is a convenient and minimally invasive treatment for glottic insufficiency. This study assessed whether injection laryngoplasty is safe under continued administration of antithrombotic drugs, and aimed to establish measurable laboratory values under which such a procedure can be safely performed.Method: This retrospective medical record review covered the period from November 2012 to June 2018. We examined 17 patients who underwent injection laryngoplasty (47 injections) under continued administration of antithrombotic drugs at the University of Tokyo Hospital. We analyzed clinical and demographic profiles, complications, and blood test values. Statistical analyses were performed regarding the risks of complications due to injection side, route of administration, and number of antithrombotic drugs.Results: No patients exhibited airway narrowing or dyspnea; however, bleeding after injection laryngoplasty was observed in 3 patients. All patients exhibited values within the optimal treatment range. There were no significant differences regarding the risks of complications due to injection side, route of administration, or number of antithrombotic drugs.Conclusions: When the platelet count, prothrombin time-international normalized ratio, and activated partial thromboplastin time were within the optimal range prior to treatment, injection laryngoplasty could safely be performed, regardless of the administration of antithrombotic drugs. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence in Japan. Although prothrombin time-international normalized ratio (PT-INR) targets for monitoring warfarin therapy in patients with nonvalvular AF (NVAF) are well defined, real-world patient characteristics and PT-INR levels remain unknown among Japanese patients with NVAF who initiate and continue warfarin (warfarin maintainers) versus those who switch from warfarin to direct oral anticoagulants (DOACs; warfarin switchers).Methods: Patients with NVAF receiving oral anticoagulants between February 2013 and June 2015 were identified using a nationwide electronic medical record (EMR) database from 69 hospitals in Japan. Demographics and characteristics of patients, PT-INR, time in therapeutic range (TTR), and frequency in range (FIR) of PT-INR between warfarin maintainers and warfarin switchers were assessed.Results: A total of 1705 patients met inclusion criteria and were examined (1501 warfarin maintainers versus 204 warfarin switchers). CHADS2, CHA2DS2-VASc, and HAS-BLED scores were comparable between groups. However, these scores were significantly higher among warfarin switchers at the time of switching than at the time of warfarin initiation. Furthermore, TTR and FIR of PT-INR were lower in warfarin switchers than in maintainers. Nevertheless, TTR and FIR were below 50% (PT-INR, 1.6-2.6) in both patient groups.Conclusions: In this EMR-based clinical study, patients who switched to DOACs had both poor or inadequate PT-INR control and higher risk factors of stroke. Many patients receiving warfarin did not achieve sufficient PT-INR therapeutic range. DOACs could be recommended in Japanese patients with NVAF with inadequate PT-INR control and increased risk of stroke. [ABSTRACT FROM AUTHOR]

Background: Warfarin, a widely used anticoagulant, interacts with various agents used in palliative care, such as oxycodone, morphine, acetaminophen, and non-steroidal anti-inflammatory drugs (NSAIDs); however, there are no reports of its interaction with methadone. We report a case of a patient receiving warfarin when methadone was introduced for pain control with monitoring of the prothrombin time-international normalized ratio (PT-INR) and deduced the pharmacological background. Case presentation: A 60-year-old male was emergently admitted to our university hospital for the sudden onset of severe back pain. Abdominal CT imaging revealed that the vertebral body of the ninth thoracic vertebra was occupied by bone metastasis and crushed, which caused his back pain. He received warfarin 3.5 mg/day for atrial fibrillation and tapentadol 100 mg p.o. daily for pain relief. The prothrombin time-international normalized ratio (PT-INR) was maintained at >2.2. The patient's history included diabetes mellitus and hypertension, but his laboratory test was unremarkable with the exception that his eGFR was 34 ml/min. Initially, a fentanyl dermal patch was used instead of tapentadol to avoid interactions with warfarin. We started concomitant administration of oxycodone and 2.4 g/day of acetaminophen while monitoring the PT-INR because acetaminophen increased the PT-INR to 2.93. A continuous intravenous infusion of oxycodone was introduced, in increments of the dose, resulting in an increase of the PT-INR to 3.41, which is required to reduce the dose of warfarin to 1.5 mg. Because of the lack of effective pain relief, methadone was introduced and the dose was gradually increased. The PT-INR was not changed and the dose of warfarin was not changed. An infusion of oxycodone and oral methadone was used to allow the patient to walk in his room, and he was later transferred to the palliative hospital. Conclusions: In an oral warfarinized patient, methadone seemed to undergo different metabolism than oxycodone. When warfarin and methadone are used together, we have to consider their interaction by comparing the competitive inhibition of CYP2C9 to the induction of CYP3A4 by methadone, because CYP3A4 metabolize various drugs including oxycodone. [ABSTRACT FROM AUTHOR]

Background Although polymyxin B cartridge hemoperfusion (PMX) has an important place in the treatment of patients with severe sepsis and/or septic shock (SS), there are few rigid indications for performing PMX a second time.The objective of the study was to investigate the clinicolaboratory characteristics (CCs) showing the most significant change from the first to the second PMX and associated with 28-d mortality in patients with SS. Methods Between April 2006 and March 2008, 78 patients with SS who had received two sessions of PMX in a prospectively collected multicenter collaboration study were enrolled. Univariate and multivariate analyses using the differences in the values of individual CCs (Δ-CCs) were performed to assess the CCs showing the most significant change in value associated with 28-d mortality. The Δ-CC was defined as: Δ 2nd-1st -CC = value of the CC just before the second PMX − value of the CC just before the first PMX. Results Among 28 Δ 2nd-1st -CCs, 10 Δ 2nd-1st -CCs were selected by using receiver operating characteristic (ROC) curve analyses. The results of multivariate analysis using adequate 8 Δ 2nd-1st -CCs that had been selected by univariate analyses revealed that only Δ 2nd-1st -prothrombin time–international normalized ratio (PT-INR) (≤0.16/>0.16; hazard ratio = 6.562; 95% CI = 1.525–28.23; P = 0.012) was associated with 28-d mortality. Survival curve analysis demonstrated a significant difference in 28-d mortality between patients with a lower (≤0.16) and a higher (>0.16) Δ 2nd-1st -PT-INR ( P < 0.001). Conclusions Patients with exacerbation of PT-INR (>0.16) after initial PMX are unlikely to benefit clinically from a second PMX for treatment of SS. [ABSTRACT FROM AUTHOR]

Aim The number of patients with autoimmune hepatitis ( AIH) showing acute presentation has increased. This study aimed to assess their prognosis. Methods A survey of AIH patients by sending questionnaires was performed, and 96 patients showing acute presentation were investigated. Results The median age was 58 years and 78 patients (81%) were female. Eighty-four patients (88%) were positive for antinuclear antibody and/or anti-smooth muscle antibody. The median serum immunoglobulin G level was 2252 mg/ dL. Twenty-five patients (26%) showed histological acute hepatitis. As initial treatment, 88 patients (92%) were treated with corticosteroid, and 28 of them received pulse steroid treatment. Overall, 11 patients (11%) reached fatal outcomes (nine death and two liver transplantation). Patients with histological acute hepatitis showed higher serum bilirubin levels, lower prothrombin activities and higher prothrombin time-international normalized ratios ( PT-INR) and reached fatal outcomes more frequently. With a multivariate logistic regression analysis, prothrombin activity and PT-INR at presentation was associated with fatal outcomes. Nine of 13 patients (69%) showing prothrombin activity of 40% or lower at presentation and nine of 19 patients (47%) showing PT-INR of 1.5 or higher reached fatal outcomes. Furthermore, of 13 patients showing prothrombin activity of 40% or lower and/or PT-INR of 1.5 or higher at presentation who were treated with pulse steroid treatment, four (31%) died from infectious disease. Conclusion Prothrombin activity and PT-INR are prognostic factors for AIH showing acute presentation. Physicians should pay attention to the development of infectious disease when pulse steroid treatment is performed. [ABSTRACT FROM AUTHOR]

Purpose: The present study investigated clinical characteristics including plasma brain natriuretic peptide (BNP) among transient ischemic attack (TIA) and stroke patients with atrial fibrillation (AF). Methods: We prospectively enrolled 227 consecutive patients with AF within 24 h of onset of TIA or stroke, and plasma BNP was measured on admission. Patients were divided into 2 groups: TIA and stroke groups. The factors associated with TIA were investigated by multivariate logistic regression analysis. Results: 21 patients (9.3%) were diagnosed with TIA, and 206 patients (90.7%) with stroke. The plasma BNP level of the TIA group was significantly lower than that of the stroke group [median (interquartile range) 86.5 (72.7-189.0) pg/ml vs. 269.0 (146.0-432.0) pg/ml, p = 0.0002]. The optimal cutoff level, sensitivity, and specificity of BNP levels to distinguish the TIA group from the stroke group were 120 pg/ml, 79.1 and 66.7%, respectively. Multivariate logistic regression analysis demonstrated that pre-admission warfarin use (OR 3.7; 95% CI 1.178-11.570, p = 0.0250), glucose of ≤120 mg/dl (OR 5.1; 95% CI 1.629-16.238, p = 0.0052) and a plasma BNP of ≤120 pg/ml (OR 6.1; 95% CI 1.967-18.931, p = 0.0017) were independently associated with TIA. Conclusions: In AF patients, the BNP value on admission is lower in those with TIA than in those with stroke. Thus, cardiac function may be associated with neurological severity at the onset of TIA and stroke. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Despite the literature indicating adverse interactions between warfarin and cytotoxic agents, whether such an interaction occurs when warfarin and gefitinib are used concomitantly is unknown. We analyzed the prevalence of the concomitant use of warfarin and gefitinib, and the incidence of prothrombin time-international normalized ratio (PT-INR) alterations or adverse interactions in concomitant users of warfarin and gefitinib. We conducted a retrospective study of patients with non-small cell lung cancer treated at the Kitasato University Hospital who received concomitant warfarin and gefitinib between September 2002 and January 2007. Medical information, including the indication for warfarin use, warfarin dosing and dosing changes, and exposure to gefitinib were collected from computerized databases and medical records. Twelve (4.1%) of 296 patients treated with gefi— tinib received warfarin. PT-INR elevation occurred in 6 patients (50.0%). Two (16.7%) of the 12 patients had liver metastases. Liver dysfunction was associated with PT-INR elevation ( P = 0.0100). As there is a possibility of PT-INR abnormalities occurring during the concomitant use of gefitinib and warfarin, clinicians should be aware of this interaction. Because of the potentially severe consequences of this interaction, close monitoring of PT-INR and warfarin dose adjustment are recommended for patients receiving warfarin and gefitinib, especially during the first 2 weeks in the beginning of warfarin therapy. [ABSTRACT FROM AUTHOR]

Warfarin is a representative anticoagulant with large interindividual variability. The published kinetic-pharmacodynamic (K-PD) model allows the prediction of warfarin dose requirement in Swedish patients; however, its applicability in Japanese patients is not known. We evaluated the model's predictive performance in Japanese patients with various backgrounds and relationships using Bayesian parameter estimation and sampling times. A single-center retrospective observational study was conducted at Tokyo Women's Medical University, Medical Center East. The study population consisted of adult patients aged >20 years who commenced warfarin with a prothrombin time-international normalized ratio (PT-INR) from June 2015 to June 2019. The published K-PD model modified by Wright and Duffull was assessed using prediction-corrected visual predictive checks, focusing on clinical characteristics, including age, renal function, and individual prediction error. The external dataset included 232 patients who received an initial warfarin daily dose of 3.2 ± 1.28 mg with 2278 PT-INR points (median [range] follow-up period of 23 d [7-28]). Prediction-corrected visual predictive checks carried a propensity for underprediction. Additionally, age >60 years, body mass index ≤25 kg/m 2 , and estimated glomerular filtration rate ≤60 mL/min/1.73 m 2 had a pronounced tendency to underpredict PT-INR. However, Bayesian prediction using four prior observations reduced underprediction. To improve the prediction performance of these special populations, further studies are required to construct a model to predict warfarin dose requirements in Japanese patients.

Anticoagulation is central to the management of thrombotic antiphospholipid syndrome (APS). The standard anticoagulant treatment for thrombotic APS is life-long warfarin or an alternative vitamin K antagonist. The role of direct oral anticoagulants for thrombotic APS is not established due to the lack of definitive evidence and has recently been addressed in international guidance. Other anticoagulant options include low molecular weight heparin, unfractionated heparin, and fondaparinux. In APS patients, lupus anticoagulant can affect phospholipid-dependent coagulation monitoring tests, so that they may not reflect true anticoagulation intensity. Accurate assessment of anticoagulation intensity is essential, to optimize anticoagulant dosing and facilitate thrombus resolution; minimize the risk of recurrent thrombosis or bleeding; inform assessment of whether recurrent thrombosis is related to breakthrough thrombosis while on therapeutic anticoagulation, subtherapeutic anticoagulation, non-adherence, or spurious results; and guide the management of bleeding. Knowledge of anticoagulant intensity also informs assessment and comparison of anticoagulation regimens in clinical studies. Considerations regarding anticoagulation dosing and/or monitoring of thrombotic APS patients underpin appropriate management in special situations, notably APS-related severe renal impairment, which can occur in APS or APS/systemic lupus erythematosus-related nephropathy or catastrophic APS; and APS-related thrombocytopenia. Anticoagulant dosing and monitoring in thrombotic APS patients also require consideration in anticoagulant-refractory APS and during pregnancy. In this review, we summarize the tests generally used in monitoring anticoagulant therapy, use of the main anticoagulants considered for thrombotic APS, lupus anticoagulant effects on anticoagulation monitoring tests, and strategies for appropriate anticoagulant monitoring in thrombotic APS., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of InternationalSociety on Thrombosis and Haemostasis.)

Warfarin (WF) shows a number of interactions with other drugs, which alter its anticoagulant effects. The albumin binding interaction is one such pharmacokinetic mechanism of drug interaction with WF, which induces a rise in the free WF concentration and thus increases the risk of WF toxicity. Teicoplanin (TEIC) is an anti-methicillin-resistant Staphylococcus aureus drug, which also binds strongly to albumin in the plasma. Therefore, co-administration of TEIC may displace WF from the albumin binding site, and possibly result in a toxicity. The present study was performed to investigate the drug-drug interaction between WF and TEIC in comparison with controls treated with vancomycin (VCM), which has the same spectrum of activity as TEIC but a lower albumin binding ratio.The records of 49 patients treated with WF and TEIC or VCM at Fukuoka University Hospital between 2010 and 2015 were retrospectively reviewed. These 49 patients consisted of 18 treated with TEIC in combination with WF, while 31 received VCM in combination with WF. Prothrombin time-international normalized ratio (PT-INR) showed a significant increase of 80.9 (52.0-155.3) % after co-administration of TEIC with WF. In contrast, the rate of PT-INR elevation associated with VCM plus WF was 30.6 (4.5-44.1) %. These observations suggested that TEIC can cause a rise in free WF concentration by albumin binding interaction. Therefore, careful monitoring of PT-INR elevation is necessary in patients receiving WF plus TEIC.

Several case studies have reported a possible drug interaction between warfarin and tramadol where tramadol coadministration enhanced the antithrombotic effects of warfarin. To assess this drug interaction, changes in prothrombin time-international normalized ratio (PT-INR) before and after tramadol coadministration were investigated in patients receiving warfarin. For this study, we examined 54 patients (male/female: 22/32, 68.4±12.7 years) who were being treated with warfarin for deep vein thrombosis, atrial fibrillation, arteriosclerosis obliterans, congestive heart failure, and other vascular diseases. Significant increases in PT-INR were observed 9.5 (1-118) d after coadministration of tramadol (1.81±0.56 vs. 2.47±1.10, p<0.01). Twenty-eight patients (PT-INR increased group) with PT-INR elevation of greater than 0.5 or dose reduction of warfarin after coadministration of tramadol were compared with other groups of patients to find drug interaction risk factors. Logistic regression analysis revealed that lower levels of albumin (3.5 g/dL or less) [odds ratio (OR) 22.1; 95%CI 2.9-169.9]; lower eGFR (50 mL/min or less) (OR 7.7; 95%CI 1.4-42.0); and PT-INR before tramadol coadministration (OR 38.2; 95%CI 3.7-397.6) were characteristic of the PT-INR increased group. These results suggest that tramadol coadministration enhanced the antithrombotic effects of warfarin in patients with higher PT-INR, lower albumin levels and decreased renal function as the risk factors for this drug interaction.

Purpose: To investigate the treatment and long-term outcome of portal vein thrombosis (PVT) after partial splenic embolization (PSE)., Materials and Methods: From January 2006 to December 2011, 145 patients with hypersplenism caused by cirrhotic portal hypertension underwent PSE. In 11 cases, PVT was detected 13-42 days after PSE. Among the 11 patients, 5 underwent anticoagulant therapy because of clinical symptoms, and 6 did not receive anticoagulation because they were symptom-free (4 patients) or experienced variceal bleeding (2 patients). The long-term follow-up data from these 11 patients were analyzed retrospectively., Results: The 11 patients with PVT had a mean splenic infarction ratio of 71.5%. The mean duration of follow-up was 37.6 months. During the follow-up period, none of the 5 patients who underwent anticoagulation developed variceal hemorrhage despite presenting with large esophagogastric varices. Four of the five patients achieved complete resolution of thrombosis, and one did not develop thrombus progression. However, among the 6 patients who did not undergo anticoagulation, 2 developed esophagogastric variceal hemorrhage secondary to thrombus progression, 3 developed cavernous transformation of the portal vein and variceal progression, and 1 had partial calcification of the thrombus. Two patients who had variceal bleeding or rebleeding underwent a transjugular intrahepatic portosystemic shunt. Complete recanalization of the portal vein was achieved after the procedures., Conclusions: PVT is a severe, potentially fatal complication of PSE. Early detection of PVT and prompt anticoagulation are effective to avoid serious consequences of PVT., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The relationship between the intensity of anticoagulation at the onset of acute cardioembolic stroke and clinical outcome after stroke is unclear. Here, we elucidated the relationship between prothrombin time-international normalized ratio (PT-INR) values on admission and clinical outcomes in patients with acute cardioembolic stroke., Methods: A total of 602 patients from the Fukuoka Stroke Registry in Japan who had been treated with warfarin but developed cardioembolic stroke were enrolled. The patients were classified into 3 groups according to their PT-INR values on admission: PT-INR <1.50, 411 patients; PT-INR 1.50 to 1.99, 146 patients; and PT-INR ≥2.00, 45 patients. The associations between PT-INR categories and severe neurological deficits (National Institutes of Health Stroke Scale ≥10) on admission and poor functional outcome (modified Rankin scale 4-6) at discharge were investigated using a logistic regression analysis., Results: Neurological deficits on admission were less severe, and functional outcome at discharge was more favorable as the PT-INR level on admission increased. The multivariate analysis revealed that severe neurological deficits were inversely associated with PT-INR on admission (PT-INR 1.50-1.99: odds ratio, 0.66; 95% confidence interval, 0.43-1.00; PT-INR ≥2.00: odds ratio, 0.41; 95% confidence interval, 0.20-0.83; compared with a reference group of PT-INR <1.50). Poor functional outcome was less likely in patients with PT-INR ≥2.00 (odds ratio, 0.20; 95% confidence interval, 0.06-0.55) after adjustment for confounders., Conclusions: Prestroke PT-INR ≥2.0 is associated with favorable clinical outcomes after acute cardioembolic stroke.