Prothrombin Time-international Normalized Ratio Research Articles

Causes of Ischemic Stroke in Patients with Non-Valvular Atrial Fibrillation

Background: Oral anticoagulants (OACs) reduce the incidence of embolic events associated with non-valvular atrial fibrillation (NVAF); however, ischemic stroke can still occur in such patients. Although there are various causes of ischemic stroke in patients with NVAF, their medication status at onset has scarcely been studied. This retrospective study aimed to determine the underlying causes of ischemic stroke in patients with NVAF in relation to pre-stroke anticoagulation. Methods: Among Japanese patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to May 2013, 1,302 patients with NVAF who had been hospitalized within 24 h of onset were included in this study, and their backgrounds, pre-stroke use of OACs and prothrombin time-international normalized ratio (PT-INR) on admission were investigated. Strokes were regarded as being non-cardioembolic (CE) type when causes other than NVAF had been identified. The sub-therapeutic range (TR) for warfarin was defined according to Japanese guidelines for pharmacotherapy of atrial fibrillation. Results: Atrial fibrillation had been diagnosed prior to onset of stroke in 704 of 1,302 patients (54%). However, it had not been detected before or on admission, but identified later during hospitalization in 270 patients (21%). Of the patients who had atrial fibrillation on admission but had not been diagnosed as having it, 108 (8%) had not received any medication before onset of stroke and 220 (17%) had received medications other than OACs. OACs had been administered to 415 (59%) of the patients with known atrial fibrillation. The proportion of pre-stroke CHADS₂ or CHA₂DS₂-VASc scores ≥1 ranged from 93 to 99% depending on whether atrial fibrillation had been diagnosed or anticoagulation therapy administered before stroke onset. The PT-INR was in the sub-TR on admission in 283 of 399 patients (71%) receiving warfarin. Male sex, smoking and previous stroke were more prevalent in patients with values within or over the TR of PT-INR than in those in the sub-TR. Non-CE stroke was more prevalent in patients with values above the lower therapeutic limit of the recommended PT-INR than in those in the sub-TR (p < 0.001). The number of CE strokes was much smaller in patients with high admission PT-INR values; this was not observed for non-CE ischemic strokes (p < 0.001). Conclusions: In the clinical setting, under-diagnosis, underuse and sub-therapeutic doses of OACs are major causes of ischemic stroke in patients with NVAF. However, non-CE ischemic strokes may develop in patients receiving therapeutic doses of warfarin.

Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.

Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann-Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70%) showed increase in PT-INR after ezetimibe treatment (1.96±0.45 to 2.20±0.61, p<0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p=0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34±0.54 vs. 0.06±0.36, p=0.03). There was an increase in the TTR (52±26 to 61±23%, p<0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6%) to 20 times of 695 examination days (3%), p=0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.

Use of systemic low-dose unfractionated heparin in microvascular head and neck reconstruction: Influence in free-flap outcomes

Background: Intravenous heparin administration is used to prevent thrombosis in free-flap transfer. However, it is unknown whether the use of heparin affects free-flap survival. The purpose of this study is to investigate the effect of heparin in free flap transfer. Methods: Two hundred and six patients who received ablative surgery for head and neck cancer were classified into three groups. Group A received ablative surgery, neck dissection, and free-flap reconstruction, and postoperatively they were administered continuous intravenous unfractionated heparin (5000–10 000 units/day) until postoperative day 7 (POD7); group B received the same procedures as group A but without heparin; group C received only ablative surgery and neck dissection without heparin. As indicators of coagulation time, the prothrombin time-international normalised ratio (PT-INR) and the activated partial thromboplastin time (APTT) were measured, before surgery and on POD1, 3, and 7. Flap failure, bleeding, haematoma formation, re-exploration, and thromboembolic events were recorded. Results: The PT-INR and APTT were 1.3–1.5-times longer in group A (p < 0.01), and 1.3-times longer (p < 0.01) in group B. The PT-INR and APTT were higher in groups A and B than C (p < 0.01). The free-flap success rate was not affected. Only the incidence of haematoma was increased in group A (p = 0.04). Conclusion: Heparin increased the haematoma formation, but did not change the incidence of free-flap failure. Thus, the intravenous low-dose heparin use does not affect microvascular flap survival.

Is the HAS-BLED score useful in predicting post-extraction bleeding in patients taking warfarin? A retrospective cohort study

ObjectiveUnexpected post-extraction bleeding is often experienced in clinical practice. Therefore, determining the risk of post-extraction bleeding in patients receiving anticoagulant therapy prior to surgery is beneficial. This study aimed to...

Home management of INR in the public health system: feasibility of self-management of oral anticoagulation and long-term performance of individual POC devices in determining INR.

The home prothrombin time/international normalized ratio (PT/INR) self-management could be convenient for patients, enhancing treatment compliance and improving the quality of the oral anticoagulation. However, patient self-management (PSM) of oral anticoagulation may not be feasible for up to half of the patients due to cognitive or educational issues. In the present study, we aimed to evaluate the feasibility of a PSM program in a public health medical center that provides care for low-income patients. We also aimed to determine the accuracy of individual point-of-care devices (CoaguChek XS(®)) during long-term of home manipulation. Patients' time-in-therapeutic range (TTR) and perception of quality of life, were evaluated at scheduled study-visits to the center. Additionally, the accuracy of individual CoaguChek XS(®) was evaluated in comparison to the standard automated coagulometer at scheduled study-visits to the center. Twenty-five patients were included in the PSM program. The median TTR of patients was 75% before inclusion, 72% at 3months, 75% at 6months and 100% at 12months after the beginning of self-management (P=0.14).The median DASS scores were 64, 63, 61.5 and 71.5 before inclusion and at 3, 6 and 12months, respectively (P=0.09). One hundred paired INR values were obtained. Correlation between INR values delivered by individual CoaguChek XS(®) and the automated coagulometer was 94% and the mean result bias was 0.07 INR units. The coefficient of correlation and the mean bias between methods was stable during 24months of follow-up. The present study suggests that PSM is feasible for patients treated in the public health system and that the results delivered by CoaguChek XS(®) have long-term reliability.

Risk of major bleeding at different PT-INR ranges in elderly Japanese patients with non-valvular atrial fibrillation receiving warfarin: a nested case-control study.

BackgroundDebate continues about the optimal anticoagulation level for elderly Japanese patients with non-valvular atrial fibrillation (NVAF) receiving warfarin. The Japanese Circulation Society guideline has recommended prothrombin time-international normalized ratios (PT-INR) of 1.6 – 2.6 for elderly patients and 2.0 – 3.0 for non-elderly patients, because previous observational studies indicated increased risk of bleeding when the ratio exceeded 2.6. We aimed to reappraise the relationship between PT-INR and the risk of major bleeding in elderly Japanese patients.MethodsFrom the electronic medical records, we selected a cohort of elderly (age ≥ 70 years) Japanese patients with NVAF who were prescribed warfarin for the prevention of thromboembolic diseases between November 2010 and March 2014 at Kanto Rosai Hospital. We identified those who developed major bleeding (cases). For each case, we randomly selected two matched controls by adopting a risk-set sampling method defined by calendar date, age, gender, length of warfarin administration, and the prescriber of warfarin. The risk of major bleeding in patients having PT-INR ≤ 1.49, 1.50 – 1.99, 2.00 – 2.49 (the reference), 2.50 – 2.99, and ≥ 3.00 were compared using the conditional logistic regression method. The study protocol was approved by the IRB before the study was begun.ResultsAmong the cohort of 806 elderly patients, we identified 32 cases and selected 64 matched controls. The overall incidence of major bleeding was 3.5 per 100 patient-years. The odds ratios (95 % confidence intervals) for the risk of developing major bleeding in patients with PT-INR ≤ 1.49 (n = 20), 1.50 – 1.99 (n = 32), 2.00 – 2.49 (n = 18), 2.50 – 2.99 (n = 10), and ≥ 3.00 (n = 16) were 1.0 (0.2, 5.9), 0.3 (0.1, 1.9), 1.0 (reference), 1.2 (0.2, 8.4), and 19.8 (2.0, 198.9), respectively, with a significant difference between ≥ 3.00 and reference.ConclusionsAmong elderly Japanese patients with NVAF, PT-INR 2.0 – 3.0 may be associated with a clinically permissible risk of major bleeding while PT-INR ≥ 3.00 a significant risk. Further studies are warranted to determine whether the risk of major bleeding is significantly lower for PT-INR 2.50 – 2.99 than for PT-INR ≥ 3.00.

Assessment of Drug-Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy.

Aprepitant is a known inducer of CYP2C9, the main warfarin-metabolizing enzyme. Consequently, co-administration of these two drugs may result in reduction of the anticoagulation activity of warfarin. However, the nature and degree of time-dependent changes in prothrombin time international normalized ratio (PT-INR) after aprepitant and warfarin co-treatment in patients receiving anticancer chemotherapy has not been elucidated. We retrospectively examined the changes in warfarin dose, PT-INR, and warfarin sensitivity index (WSI; average of PT-INR value/average of daily warfarin dose) during four weeks, i.e., one week before and three weeks after aprepitant administration. The mean and standard deviation values of WSI for one week before and one, two, and three weeks after the beginning of aprepitant administration were 0.51±0.22 (1.00, n=34), 0.74±0.30 (1.53±0.59, n=30), 0.38±0.15 (0.82±0.22, n=28), and 0.46±0.29 (0.87±0.23, n=24), respectively. Values in parentheses represent relative changes versus WSI of one week before and number of subjects. Although the mean value of WSI significantly increased one week after aprepitant administration compared to that at one week before the administration, it in turn significantly decreased two weeks after compared to one week before (paired t-test, p<0.05 after Bonferoni correction). In patients taking warfarin, PT-INR should be carefully monitored for at least two weeks after the beginning of aprepitant administration because it may fluctuate with both aprepitant and chemotherapy during this period.

Interaction between Warfarin and Linezolid in Patients with Left Ventricular Assist System in Japan.

The purpose of this study was to investigate the possible interaction between warfarin and linezolid in patients with a left ventricular assist system (LVAS) for the treatment of severe heart failure. Patients with LVAS who were treated with linezolid for the treatment of infections from January 2003 to March 2013 were identified from medical records. The impact of linezolid on the clotting function, as well as the dose of warfarin during the first 10 days of linezolid therapy, was investigated. The mean prothrombin time-international normalized ratio (PT-INR) and mean doses of warfarin during 7 days before and 10 days after the initiation of linezolid therapy were calculated for individual patients. The PT-INR per mg of WF dose on the previous day (X) was calculated. The warfarin dose, PT-INR, and warfarin sensitivity index (WSI) value before and after the initiation of linezolid were compared to evaluate the impact of linezolid on the effect of warfarin. Sixteen patients were enrolled in the study. Although the mean PT-INR increased from 3.74 to 4.06, no significant difference was observed (p=0.05). A significant difference was observed in the mean dose of warfarin before and after the initiation of linezolid administration, with a decrease from 3.23 to 2.69 mg/day (p=0.001). In contrast, the mean WSI value significantly increased from 1.37 to 1.82 (p=0.014). After 10 days of linezolid administration, the mean X values increased over the baseline value by 31.7%. These findings suggest that co-administration of linezolid results in increased PT-INR in patients with LVAS treated with warfarin.

Prothrombin time on admission in patients with cardioembolic stroke and intracranial hemorrhage occurring during warfarin treatment in the direct oral anticoagulant era.

Warfarin is used worldwide to prevent cardioembolic stroke (CES) in patients with atrial fibrillation even in the era of direct oral anticoagulant (DOAC). We evaluated clinical characteristics of the patients with CES and intracerebral hemorrhage (ICH) occurring during warfarin treatment, focusing on prothrombin time-international normalized ratio (PT-INR) at the occurrence. The consecutive 846 CES patients (78 ± 9 years) and 870 ICH patients (68 ± 13 years) admitted to the Hirosaki Stroke and Rehabilitation Center from April 2011 through March 2015 were studied. The antithrombotic agents administered in CES patients before the onset included antiplatelets in 146 patients (17%), warfarin in 205 (24%), DOAC in 37 (5%), and none in the other 458 (54%). Mean PT-INR within 24 hours after the onset in nonvalvular atrial fibrillation patients with warfarin was 1.34 ± 0.33 (n = 129), and 111 of them (86%) showed PT-INR value below the recommended therapeutic range in Japan. The antithrombotic agents administered in ICH patient included antiplatelets in 87 patients (10%), warfarin in 86 (10%), DOAC in 8 (1%), and none in the other 689 (79%). Mean PT-INR within 24 hours after the onset in patients with warfarin was 2.27 ± 0.62 (n = 65), and 56 of them (86%) showed PT-INR < 2.8. Thus, there is a large population with poor warfarin control complicating CES and that with good warfarin control complicating ICH, indicating limitation of warfarin treatment in the DOAC era.

Thromboelastographic Evaluation of Coagulation in Patients with Liver Disease

Background: Patients with acute and chronic liver disease have long been assumed to have a bleeding tendency on the basis of abnormal results for standard tests of hemostasis. The concept that patients with liver disease are at an increased risk of bleeding, based solely on abnormalities of conventional coagulation tests such as prothrombin time (PT) and international normalized ratio (INR), is now recognized to be an overly simplistic interpretation of an extremely complex situation. Thromboelastography (TEG) is a commercially available, rapid, point-of-care whole blood viscoelastic assay that assesses the kinetics of coagulation from initial clot formation to final clot strength in whole blood, including plasmatic and cellular components. The aim of this study was to compare TEG citrated whole blood coagulation parameters and conventional coagulation parameters in liver disease patients and in healthy controls.Methods: Between January and July 2015, we investigated citrated blood samples from 35 healthy controls and 171 adult patients with liver disease who were divided into two groups of hepatitis group (including patients with acute and chronic hepatitis) and liver cirrhosis group (including patients with liver cirrhosis with or without hepatocellular carcinoma). The parameters of clot formation, which were R (reaction time, a measure of initial fibrin formation), K (constant, indicative of clot formation time), a (angle, indicative of the rapidity of fibrin cross-linking), MA (maximal amplitude, indicative of overall clot firmness) were measured with activator, kaolin, by using TEG 5000 system (Haemonetics Corporation, USA) and CI (Coagulation Index) was derived from the R, K, α and MA. Hemoglobin, platelet count, creatinine, total bilirubin and PT INR was simultaneously measured. MELD (The Model for End-Stage Liver Disease) score for assessing the severity of liver disease was calculated by creatinine, bilirubin and PT INR.Results: A total 206 cases, 53 patients with hepatitis group, 118 patients with liver cirrhosis group, and 35 patients with control group, was enrolled. In the liver cirrhosis group, all of parameters of TEG and hemoglobin showed significant difference with those of control group. In the hepatitis group, only R time and platelet count were significant different from that of the control group. There were significant differences of all parameter, except R time, between hepatitis group and liver cirrhosis group. According to etiology, PT-INR, MELD score, platelet count, K, angle, MA, CI of autoimmune liver disease were different form liver disease of viral and other cause. All parameter of TEG were statistically significantly correlated with the number of platelets and PT INR and MELD score (Table 1).Table 1. Correlation coefficients and P value among the parameters of thromboelastography, PT INR, platelets, and MELD score Table 1PT INRPlateletsMELD scoreReaction Time (R)0.247(<0.001)-0.286(<0.001)0.157(<0.01)Constant (K)0.296(<0.001)-0.567(<0.001)0.219(<0.001)Angle (α)-0.293(<0.001)0.613(<0.001)-0.206(<0.001)Maximal Amplitude (MA)-0.348(<0.001)0.719(<0.001)-0.287(<0.001)Coagulation Index (CI)-0.364(<0.001)0.672(<0.001)-0.275(<0.001)Conclusion: The patients with liver disease with high MELD score, elevated PT INR, and thrombocytopenia demonstrated the trend to hypocoagulability and hyperfibrinolysis using TEG. TEG is considered as an additional test for investigating liver disease and predicting the prognosis in this category of patients. DisclosuresNo relevant conflicts of interest to declare.

A multicenter, prospective, observational study of warfarin-associated intracerebral hemorrhage: The SAMURAI-WAICH study

BackgroundBecause patients with warfarin-associated intracerebral hemorrhage (WAICH) have a high risk of ongoing bleeding, disability, and death, urgent coagulopathy reversal should be considered. On the other hand, thromboembolism may occur with reversal or withholding of anticoagulant therapy. The current status of acute hemostatic treatments and clinical outcomes in WAICH patients was investigated. MethodsWAICH patients admitted within 3days of onset were prospectively enrolled in 10 stroke centers. Thromboembolic and hemorrhagic complications and functional outcomes were followed-up for one year. ResultsOf 50 WAICH patients (31 men, 73±9years old) enrolled, all stopped warfarin on admission. Elevated prothrombin time-international normalized ratios (PT-INR) were normalized in 43 (86%). Anticoagulant therapy was resumed with intravenous full-dose unfractionated heparin followed by warfarin in 9 (18%), intravenous low-dose unfractionated heparin followed by warfarin in 14 (28%) and warfarin alone in 14 (28%) at a median of 2.5 (IQR 1.25–9), 4 (2–5.5) and 6 (3–11) days after onset, respectively, after emergent admission. Onset-to-admission time (per 1-hour increase; OR 0.55, 95% CI 0.19–0.84) was inversely associated with hematoma expansion. Anticoagulant therapy was resumed with intravenous full-dose unfractionated heparin in 9 (18%), low-dose heparin in 14 (28%) and warfarin alone in 14 (28%) at a median of 2.5, 4 and 6days after onset, respectively. During one-year follow-up (n=47), 11 thromboembolic and 6 hemorrhagic complications were documented. Twenty four patients showed unfavorable outcomes, corresponding to a modified Rankin Scale score of 4–6. Thromboembolic complications (OR, 10.62; 95% CI, 1.05–227.85), as well as advanced age (per 1year; OR, 1.27; 95% CI, 1.10–1.61) and higher National Institutes of Health Stroke Scale (NIHSS) score (per 1 point; OR, 1.24; 95% CI 1.07–1.55), were independently associated with unfavorable outcome. ConclusionsPT-INR normalization on admission and early anticoagulant resumption were common in WAICH patients. Thromboembolic complications were independently associated with unfavorable outcome.

Haemostatic management for oral surgery in patients supported with left ventricular assist device– a preliminary retrospective study

We investigated haemostatic management, frequency of postoperative bleeding, and prognosis of patients who had left ventricular assist devices, and who were having oral surgical procedures between April 2002 and March 2014, to identify risk factors for bleeding and find out which were the best methods of haemostasis. Medical records were examined retrospectively and we recorded details of the patients, and frequency of bleeding together with factors associated with it. Twenty-nine patients had 39 oral operations, and there were 17 bleeds (44%). The first procedure for each patient was used for statistical calculations. Duration of bleeding tended to be longer for patients with implantable devices (median (interquartile range, IQR) 12.0 (3-18) days) than for those with extracorporeal devices (median (IQR) 3.0 (1-4) days; p=0.079). There was a significantly greater difference in prothrombin time-international normalised ratio (PT-INR) before and after operation in patients who bled, whose median (range) was 0.85 (0.2-1.81), than in those who did not (median (IQR) 0.16 (-0.09-0.31) (p=0.015). There were moderate correlations with postoperative bleeding were seen for the difference between preoperative and postoperative PT-INR (r=0.479, p=0.012) and PT-INR value when bleeding (r=0.407, p=0.035). In conclusion, postoperative bleeding occurred after oral operations in 17/29 patients with left ventricular assist devices by a median (IQR) of 0.85 (0.2-1.81) of the preoperative value.

Assessing Clinical Laboratory Quality: A College of American Pathologists Q-Probes Study of Prothrombin Time INR Structures, Processes, and Outcomes in 98 Laboratories.

The anticoagulant warfarin has been identified as the second most frequent drug responsible for serious, disabling, and fatal adverse drug events in the United States, and its effect on blood coagulation is monitored by the laboratory test called international normalized ratio (INR). To determine the presence of INR policies and procedures, INR practices, and completeness and timeliness of reporting critical INR results in participants' clinical laboratories. Participants reviewed their INR policies and procedure requirements, identified their practices by using a questionnaire, and studied completeness of documentation and timeliness of reporting critical value INR results for outpatients and emergency department patients. In 98 participating institutions, the 5 required policies and procedures were in place in 93% to 99% of clinical laboratories. Fifteen options for the allowable variations among duplicate results from different analyzers, 12 different timeliness goals for reporting critical values, and 18 unique critical value limits were used by participants. All required documentation elements were present in 94.8% of 192 reviewed INR validation reports. Critical value INR results were reported within the time frame established by the laboratory for 93.4% of 2604 results, but 1.0% of results were not reported. Although the median laboratories successfully communicated all critical results within their established time frames and had all the required validation elements based in their 2 most recent INR calculations, those participants at the lowest 10th percentile were successful in 80.0% and 85.7% of these requirements, respectively. Significant opportunities exist for adherence to INR procedural requirements and for practice patterns and timeliness goals for INR critical results' reporting.

A novel quantitative assessment of whole blood thrombogenicity in patients treated with a non-vitamin K oral anticoagulant

Non-vitamin K oral anticoagulants(NOAC) negate complex patient management issues, such as frequent blood sampling, diet restriction, and drug interactions, that had to be dealt with during the warfarinonly era. However, there is no definite tool tomonitor the anticoagulant effects of NOACs, although some patients suffer from bleeding complications related to exceedingly high blood concentrations of NOACs. [1, 2] Routine tests, such as prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (APTT), can be problematic formonitoring the anticoagulant effects of all NOACs because each individual NOAC has a different characteristic chemical structure and different pharmacokinetic profile (e.g., plasma half-life and tissue penetration rate) [3]. Recently, the Total Thrombus-formation Analysis System (T-TASTM) [4,5], a microchip-based flow chamber system capable of evaluating whole blood thrombogenicity, was developed as an easy-to-use system for quantitative analysis of thrombus formation (Fig. 1A,B). In the present study, we sought to examine whether the T-TASTM was useful for the quantitative analysis of thrombogenicity in patients treated with the NOAC edoxaban (Fig. 1C, D). We recruited 20 consecutive patients (male: n = 8 [40%] and female: n=12 [60%], average age: 75.2±8.7 years)whowere scheduled

Pharmacogenetic-guided algorithms to estimate personalized dose or individual responses to anti-thrombotic drugs

Abstract Purpose Genotyping seems to be regarded as less useful than expected for predicting the inter-individual variation in drug response. We aim to improve the predictive accuracy of genotyping by developing models that also incorporate certain non-genetic factors. Study selection and results The anti-coagulant warfarin is widely used to prevent venous thromboembolic events. Although frequent monitoring of the prothrombin time international normalized ratio (PT-INR) allows an appropriate maintenance dose to be obtained for most individuals, there are some individuals for whom it is difficult to achieve the target PT-INR even when warfarin dose is increased. The anti-platelet drug clopidogrel is typically used with aspirin to prevent cardiovascular events following percutaneous coronary intervention. However, the existence of clopidogrel resistance is a major concern in Asian populations owing to the high prevalence of deficient allele of the CYP2C19 gene, which encodes a major enzyme that produces the active metabolite. Individual response to these anti-thrombotic drugs cannot be accurately predicted based on genetic factors alone. We have constructed two algorithms, one that predicts the maintenance dose of warfarin and one that estimates individual responses to clopidogrel in outpatients without a device-based platelet function test. We applied Akaike's Information Criterion to evaluate the validity of these algorithms. Conclusions In addition to genotyping data, inter-individual variation in non-genetic factors, such as clinical laboratory data, should be considered to predict drug response more accurately in each individual.

Factors related to thrombosis of gastric varix during balloon-occluded retrograde transvenous obliteration

Balloon-occluded retrograde transvenous obliteration (B-RTO) has become known as an effective treatment for gastric varices with a gastrorenal shunt. However, the appropriate duration to maintain inflation of the catheter balloon for sufficient thrombosis has been unknown. To evaluate retrospectively the factors related to the development of thrombus in gastric varices by evaluating the necessity of the addition of a sclerosing agent on the second day in overnight B-RTO. Sixty-five patients who underwent B-RTO for gastric varices with a gastrorenal shunt were studied. The B-RTO catheter was retained overnight in all patients. Incidence of and factors influencing the necessity of additional injections of a sclerosing agent on the second day were investigated. In all 65 patients (100%), B-RTO was technically successful and in 61 patients (93.8%) complete thrombosis of the gastric varices was achieved. In 46 of the 65 patients (70.8%), the sclerosing agent was added on the second day. Higher Child-Pugh score, in particular, lower serum albumin level, and higher prothrombin time-international normalized ratio (PT-INR) were significantly associated with the need for the addition of the sclerosing agent on the second day. Optimal cut-off values for the serum albumin level and PT-INR were 3.6 g/dL and 1.13, respectively. Liver function might influence the development of thrombosis of gastric varices in B-RTO. Serum albumin and PT-INR levels would provide information for deciding on the duration of retention of the B-RTO catheter to obtain sufficient therapeutic effectiveness.

Severity and Functional Outcome of Patients with Cardioembolic Stroke Occurring during Non-vitamin K Antagonist Oral Anticoagulant Treatment

Severity and functional outcome of patients with cardioembolic stroke (CE) occurring during non-vitamin K antagonist oral anticoagulant (NOAC) treatment remain uncertain. The consecutive 355 CE patients within 48hours after onset and with modified Rankin Scale (mRS) score of 1 or less before onset were studied. Of all, 262 patients were treated with no anticoagulants (non-AC), 63 with warfarin below therapeutic range of prothrombin time-international normalized ratio (PT-INR) on admission (PT-INR <1.6 [WF-Lo]), 16 with warfarin within therapeutic range (PT-INR ≥1.6 [WF-Tp]), and 14 with NOACs (9 dabigatran and 5 rivaroxaban [NOAC-DR]). We compared severity and functional outcome of CE patients among these 4 groups, especially focusing on patients during NOAC treatment. Stroke severity on admission, assessed by the National Institutes ofHealth Stroke Scale, was lower in WF-Tp (median, 5 [1-15]) and NOAC-DR (5[3-6]) than in non-AC (11 [5-19]) and WF-Lo (12 [5-19]; P=.006). Functional outcome at discharge, assessed by mRS, was favorable in WF-Tp (median, 1 [0-4]) and NOAC-DR (1 [1-2]) compared with that in non-AC (2 [1-4]) and WF-Lo (3[1-5]; P=.02), and ratios of the patients with mRS score of 1 or less were 63% and 64% versus 31% and 33%, respectively (P=.005). Multivariate analysis also showed a favorable functional outcome at discharge in WF-Tp and NOAC-DR groups. Drug management was likely associated with NOAC-associated CE. Stroke severity and functional outcome of CE patients treated with warfarin within therapeutic range and with NOACs are similar to each other, and are more favorable than those with no anticoagulants and with warfarin below therapeutic range.

A Bayesian decision support tool for efficient dose individualization of warfarin in adults and children

BackgroundWarfarin is the most widely prescribed anticoagulant for the prevention and treatment of thromboembolic events. Although highly effective, the use of warfarin is limited by a narrow therapeutic range combined with a more than ten-fold difference in the dose required for adequate anticoagulation in adults. An optimal dose that leads to a favourable balance between the wanted antithrombotic effect and the risk of bleeding as measured by the prothrombin time International Normalised Ratio (INR) must be found for each patient. A model describing the time-course of the INR response can be used to aid dose selection before starting therapy (a priori dose prediction) and after therapy has been initiated (a posteriori dose revision).ResultsIn this paper we describe a warfarin decision support tool. It was transferred from a population PKPD-model for warfarin developed in NONMEM to a platform independent tool written in Java. The tool proved capable of solving a system of differential equations that represent the pharmacokinetics and pharmacodynamics of warfarin with a performance comparable to NONMEM. To estimate an a priori dose the user enters information on body weight, age, baseline and target INR, and optionally CYP2C9 and VKORC1 genotype. By adding information about previous doses and INR observations, the tool will suggest a new dose a posteriori through Bayesian forecasting. Results are displayed as the predicted dose per day and per week, and graphically as the predicted INR curve. The tool can also be used to predict INR following any given dose regimen, e.g. a fixed or an individualized loading-dose regimen.ConclusionsWe believe that this type of mechanism-based decision support tool could be useful for initiating and maintaining warfarin therapy in the clinic. It will ensure more consistent dose adjustment practices between prescribers, and provide efficient and truly individualized warfarin dosing in both children and adults.Electronic supplementary materialThe online version of this article (doi:10.1186/s12911-014-0128-0) contains supplementary material, which is available to authorized users.

Knowledge Regarding Oral Anticoagulation Therapy among Patients with Stroke and Those at High Risk of Thromboembolic Events

Apart from atrial fibrillation, indications for oral anticoagulation common in our clinical practice include rheumatic heart disease and mechanical heart valve replacement. Evaluation of current patient knowledge regarding oral anticoagulation therapy (OAT) is the first step in improving the quality of anticoagulation therapy and patient care. The aim of the present study was to assess the knowledge regarding OAT among patients with stroke and those at high risk of thromboembolic events in a tertiary care hospital in India. A descriptive cross-sectional design was used; 240 patients on OAT because of various indications (mechanical heart valve replacement, rheumatic heart disease, atrial fibrillation, and stroke) attending the neurology and cardiology outpatient clinics and inpatient services were recruited. A structured self-developed questionnaire was used to assess the knowledge in these patients. Most patients (62.9%) were ignorant about the target prothrombin time/international normalized ratio (PT/INR) levels with only 30% having their recent INR within the target range; 50% of the patients had a poor knowledge score, and the knowledge gap was most prominent in the domains of dietary interactions followed by drug interactions, adverse effects, and PT/INR monitoring. Knowledge score also had a significant association with gender, education, monthly income, and place of residence (P < .05). Patient's knowledge about OAT was suboptimal. The findings support the need for educational interventions to improve the knowledge regarding OAT and, thereby, achieve an appropriate and safe secondary prevention of stroke.

Potential drug interaction between warfarin and linezolid.

Warfarin is known to interact with many drugs; however, there are currently no descriptions of an interaction with linezolid in the literature. It was recently brought to our attention, however, that several warfarin-medicated patients have experienced an increase in the prothrombin time international normalized ratio (PT-INR) following the administration of linezolid. We therefore performed a retrospective survey in order to investigate the possibility of an interaction between warfarin and linezolid. The survey items included age, gender, underlying disease, type of surgery, type of infectious disease, duration of linezolid administration, laboratory values and the dose of warfarin. The PT-INR was observed over time before treatment and at days 4 or 5 and 10, completion and one week after the end of concomitant therapy. Patients The subjects included six patients who were recovering from recent heart-related surgery. The PT-INR increased from 1.62±0.32 before concomitant linezolid administration to 3.00±0.83 at day 4 or 5 after concomitant administration (p<0.01) and significantly decreased from 1.65±0.45 at the completion of the regimen to 1.26±0.1 one week later (p<0.05). With respect to the relationship between the dose of warfarin and the PT-INR in five cases, the PT-INR increased following concomitant linezolid treatment in all cases. Although it has been reported that linezolid does not influence the metabolism or protein binding of warfarin, our data showed potential drug interactions between warfarin and linezolid. Our data suggest that PT-INR monitoring after the completion of concomitant warfarin and linezolid therapy is important.