Impact of anticoagulation status on recanalization and outcome of cerebral venous thrombosis.

Effective anticoagulation status may determine the recanalization and outcome of cerebral venous thrombosis (CVT). We report impact of anticoagulation status on recanalization and outcome of CVT. This is a retrospective study on 126 patients with CVT diagnosed on magnetic resonance venography (MRV). Their clinical features and risk factors were noted. The data were retrieved from a prospectively maintained registry, and international normalized ratio (INR) was noted after discharge till 3 months. All the patients were on acenocoumarol. Based on INR value, patients were categorized as Group A (effective anticoagulation INR within the therapeutic range or above) and Group B (ineffective anticoagulation INR > 50% below the therapeutic range). A repeat MRV at 3 months was done for recanalization. Outcome at 3 months was evaluated using modified Rankin Scale (mRS), and categorized as good (mRS ≤ 2) and poor (mRS 2 or more) 101(80.2%) patients were in group A and 25(19.8%) in group B. Their demographic, risk factors, magnetic resonance imaging (MRI) and MRV findings were comparable. On repeat MRV, recanalization occurred in 22/24(91.7%); 15(88%) in group A and 7(100%) in group B. Recanalization was independent of coagulation status. Seven (5.6%) patients died and 107(84.9%) had good outcome; 85(84.2%) in group A and 22(88%) in group B. Kaplan Meier analysis also did not reveal survival or good outcome benefits between the groups. In CVT, outcome and recanalization at 3 months are not dependent on coagulation status. Further prospective studies are needed regarding duration of anticoagulant and its impact on recanalization and outcome.

The experience of Hamad General Hospital collaborative anticoagulation clinic in Qatar during the COVID-19 pandemic.

Hamad General Hospital Anticoagulation Clinic is one of the largest collaborative-practice clinics of its type in Qatar. The patients being followed at this clinic are typically complex and vulnerable. During the coronavirus disease 2019 pandemic, measures were implemented at the clinic to minimize the exposure of patients and healthcare providers to the acute respiratory syndrome coronavirus-2 and to promote social distancing. These measures included extending INR-recall period, transitioning to direct oral anticoagulant drugs whenever feasible, home visits to elderly and immunocompromised patients for INR testing, establishing an anticoagulation hotline, and relocation of warfarin dispensing from the main pharmacy to the anticoagulation clinic. In addition, the clinic shifted its multidisciplinary team meetings onto an online platform using Microsoft Teams. Telehealth consultations were extensively utilized to closely follow up with the patients and ensure that anticoagulation efficacy and safety remained optimal. The aim of this paper is to share our experience and describe the measures adopted by the clinic as part of the Hamad Medical Corporation response to the emerging situation.

Evaluation of dosing and safety outcomes of low-dose prophylactic warfarin in children after cardiothoracic surgery.

PURPOSE: Prophylactic warfarin with an International Normalized Ratio (INR) goal of 1.5 to 2.0 is one antithrombotic therapy utilized in children after cardiothoracic surgery (CTS); published sources suggest a dose of 0.1 mg/kg per day to achieve this goal. However, few studies have evaluated dosing in this population. The purpose of this study was to evaluate dosing and safety outcomes in children receiving warfarin after CTS. METHODS: A descriptive, retrospective review was conducted to evaluate warfarin dosing and INR outcomes in patients 18 years of age or younger who underwent CTS and received prophylactic warfarin with an INR goal of 1.5 to 2.0 from January 2014 through December 2018. The primary objective was to determine the median initial warfarin dose. Secondary objectives included identifying the percentage of documented INR values that were outside the therapeutic range, the percentage of patients with therapeutic INRs at discharge, and the 30-day readmission rate. RESULTS: Twenty-six patients were included in the review. The median initial warfarin dosage was 0.07 mg/kg/d (interquartile range [IQR], 0.05-0.10 mg/kg/d). Of the total of 177 INR values collected during the entire study period, 67 (37.9%) were therapeutic, 64 (36.2%) were subtherapeutic, and 46 (26.0%) were supratherapeutic. Eighteen patients (69.2%) had at least 1 supratherapeutic INR at any point during the study period, most frequently on days 2 through 4 of therapy. At discharge, 11 patients (42.3%) had therapeutic INRs. Four patients (15.4%) were readmitted within 30 days, with bleeding documented in 2 patients during their readmission. CONCLUSION: The majority of patients received an initial warfarin dose less than that specified in published recommendations but still had a supratherapeutic INR at least once during the study period. When initiating warfarin after CTS, a dosage of <0.1 mg/kg per day and frequent monitoring may be needed to achieve an INR goal of 1.5 to 2.0.

Transjugular Liver Biopsy: Safe Even in Patients With Severe Coagulopathies and Multiple Biopsies.

OBJECTIVES: To investigate the safety profile and diagnostic efficacy of transjugular liver biopsy (TJLB), with a focus on patients with severe coagulopathies and with multiple biopsies. METHODS: Clinical, laboratory, and demographic information was collected on 1,321 TJLBs in 932 patients (mean age 43.5 ± 23.2 years) performed between January 2009 and May 2017 to determine the diagnostic success rate and incidence of both major and minor complications in the 3-day and 30-day period post-biopsies. These outcomes were also analyzed for severely coagulopathic patients and a subgroup of patients who underwent multiple biopsies. RESULTS: The overall success rate (diagnostic yield) of the TJLB procedure was 97.7% (1,291/1,321). Overall, the major and minor complication rates were 1.0% (13/1,321) and 9.5% (126/1,321), respectively. In patients with multiple biopsies, the overall complication rate was similar to the entire study cohort, which was 10.4% (57/550). Patients were also stratified according to the platelet counts of 0-50, 51-100, 101-200, 201-300 and >300 × 10 platelets/µL. The overall complication rates were 8.0% (10/124), 11.6% (36/310), 9.9% (54/547), 11.9% (28/235), and 14.3% (11/77), respectively, and these were not statistically significant from each other. Patients were also stratified by international normalized ratio into 0-1, 1.1-2, 2.1-3, and >3. The overall complication rates of these patients were 8.0% (19/237), 11.8% (113/954), 16.3% (7/43), and 0% (0/9), respectively, and were not statistically significant from each other. DISCUSSION: TJLB is a highly efficacious, well-tolerated and safe procedure. It can be safely performed multiple times in the same patient or in critically ill, severely coagulopathic patients with no significant increase in the rate of complication while maintaining an extremely favorable diagnostic yield.

Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations.

BACKGROUND: Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown. METHODS: Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC50) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients. RESULTS: Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p < 0.01). EC50 showed a greater racial difference than CL(S) [1.03, 1.70 and 2.76 µg/mL for Asian, White and African American patients, respectively, p < 0.01). Significant predictors of INR included demographic/clinical (age, body weight, creatinine clearance and sex) and genotypic (CYP2C9*3,*8 and VKORC1 -1639G>A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 -1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4. CONCLUSIONS: Although there were contrasting racial differences in CL(S) and EC50 that impacted on the INR, the racial difference in EC50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.

Prognostic significance of abnormal hematological parameters in severe traumatic brain injury requiring decompressive craniectomy.

OBJECTIVE: Hematological abnormalities after severe traumatic brain injury (TBI) are common, and are associated with a poor outcome. Whether these abnormalities offer additional prognostic significance over and beyond validated TBI prognostic models is uncertain. METHODS: This retrospective cohort study compared the ability of admission hematological abnormalities to that of the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials) prognostic model to predict 18-month neurological outcome of 388 patients who required a decompressive craniectomy after severe TBI, between 2004 and 2016, in Western Australia. Area under the receiver operating characteristic (AUROC) curve was used to assess predictors' ability to discriminate between patients with and without an unfavorable outcome of death, vegetative state, or severe disability. RESULTS: Of the 388 patients included in the study, 151 (38.9%) had an unfavorable outcome at 18 months after decompressive craniectomy for severe TBI. Abnormalities in admission hemoglobin (AUROC 0.594, p = 0.002), plasma glucose (AUROC 0.592, p = 0.002), fibrinogen (AUROC 0.563, p = 0.036), international normalized ratio (INR; AUROC 0.645, p = 0.001), activated partial thromboplastin time (AUROC 0.564, p = 0.033), and disseminated intravascular coagulation score (AUROC 0.623, p = 0.001) were all associated with a higher risk of unfavorable outcome at 18 months after severe TBI. As a marker of inflammation, neutrophil to lymphocyte ratio was not significantly associated with the risk of unfavorable outcome (AUROC 0.500, p = 0.998). However, none of these parameters, in addition to the platelet count, were significantly associated with an unfavorable outcome after adjusting for the IMPACT predicted risk (odds ratio [OR] per 10% increment in risk 2.473, 95% confidence interval [CI] 2.061-2.967; p = 0.001). After excluding 8 patients (2.1%) who were treated with warfarin prior to the injury, there was a suggestion that INR was associated with some additional prognostic significance (OR 3.183, 95% CI 0.856-11.833; p = 0.084) after adjusting for the IMPACT predicted risk. CONCLUSIONS: In isolation, INR was the best hematological prognostic parameter in severe TBI requiring decompressive craniectomy, especially when patients treated with warfarin were excluded. However, the prognostic significance of admission hematological abnormalities was mostly captured by the IMPACT prognostic model, such that they did not offer any additional prognostic information beyond the IMPACT predicted risk. These results suggest that new prognostic factors for TBI should be evaluated in conjunction with predicted risks of a comprehensive prognostic model that has been validated, such as the IMPACT prognostic model.

Warfarin Patients With Anemia Show Trend of Out-of-Range International Normalized Ratio Frequency With Point-of-Care Testing in an Anticoagulation Clinic.

INTRODUCTION: Many factors influence international normalized ratio (INR); however, few studies have examined the impact of anemia in warfarin patients. The primary objective of this study was to explore the relationship between in-clinic anemia and the control of INR within an anticoagulation clinic. METHODS: A retrospective chart review was performed on a random sample of patients seen in an academic medical center pharmacy-managed anticoagulation clinic. Hemochron® Signature Elite machine was utilized to monitor point-of-care (POC) INR. In-clinic anemia was defined as hematocrit <32%. Statistical analyses were conducted using STATA MP a webbased platform ( https://www.stata.com/statamp/ ). RESULTS: Of the 300 patients analyzed, 45 (15%) patients had in-clinic anemia. Patients with in-clinic anemia were more likely to be younger (P < .05), female (P < .05), and have a diagnosis of sickle cell disease or anemia (P < .05). In the unadjusted logistic regression model, patients with in-clinic anemia were less likely to have an in-range INR ( OR: 0.52; 95% CI: 0.27-0.98). The adjusted regression model did not show significance. CONCLUSION: Study results suggest that in-clinic anemia may be more prevalent among younger, female patients prescribed warfarin, and patients diagnosed with in-clinic anemia may be a risk factor for out-of-range INR. Pharmacists practicing in anticoagulation clinics can incorporate this information into patient care practice in efforts to maintain optimal management.

Outcomes of warfarin therapy managed by pharmacists via hospital anticoagulation clinic versus online anticoagulation clinic.

Background In response to the recognized difficulty in the management of patients on anticoagulation therapy, anticoagulation management services were developed in both hospital anticoagulation clinics (HACs) and an online anticoagulation clinic (OAC) by a pharmacist. Objective To compare monitoring outcomes and complications of warfarin therapy managed by pharmacists via hospital or on-line. Setting The anticoagulation clinic of Fujian Medical University Union Hospital, China. Method A retrospective, observational cohort study was used to compare patients managed via hospital  to those managed o-line between December 2015 and 2016. The primary outcome was the percentage of time in the therapeutic range (TTR). The secondary outcomes were the incidence rates of hemorrhagic events, thrombotic events and extreme international normalized ratio (INR) values. Results A total of 152 patients were evaluated; 70 patients managed in a HAC were compared to 82 patients managed via an OAC. There were no significant differences in the TTR (78.9 vs. 74.0%, P = 0.393) and adverse events [major bleeding events (0 vs. 1.2%, P = 1.000), minor bleeding events (10.0 vs. 9.8%, P = 0.960), thromboembolic events (0 vs. 0%, P = 1.000), warfarin-related emergency visits (2.9 vs. 3.7%, P = 1.000)], warfarin-related hospital admissions (0 vs. 1.2%, P = 1.000), and the incidence of subtherapeutic (3.0 vs. 3.8%, P = 0.148), and extreme total (8.4 vs. 5.8%, P = 0.135), between the groups managed via HAC and OAC. Patients managed in the HAC were more stable on warfarin, with a higher percentage of INR values within the target therapeutic range (80.2 vs. 71.9%, P = 0.005) and a lower incidence of supratherapeutic INR values (8.4 vs. 18.5%, P = 0.001) compared to patients managed via OAC. Conclusion The management of oral anticoagulation therapy on-line yielded similar clinical outcomes compared to that achieved by management via the hospital, although the incidence of supra-therapeutic INR values was increased.

Clinical characteristics and prevalence of adrenal insufficiency in hemodynamically stable patients with cirrhosis.

It is well known that adrenal insufficiency is common in septic shock or hemodynamically unstable patients. But, there is as yet no sufficient clinically significant data about the exact prevalence or differences in the cause of cirrhosis with adrenal insufficiency. To investigate adrenal insufficiency prevalence in hemodynamically stable patients with cirrhosis and determine differences based on cirrhosis severity or etiology.From July 2011 to December 2012, 69 hemodynamically stable patients with cirrhosis without infection admitted at Hallym University Medical Center were enrolled. Adrenal insufficiency was defined as a peak cortisol level < 18 µg/dL, 30 or 60 minutes after 250 µg Synacthen injection.The study included 55 male patients (79.7%), and the mean age was 57.9 ±â€Š12.9 years. Cirrhosis etiology was alcohol consumption, HBV, HCV, both viral and alcohol related, and cryptogenic in 49, 15, 7, 11, 9 patients, respectively. Adrenal insufficiency occurred in 24 patients (34.8%). No differences were found in age, sex, mean arterial pressure, heart rate, HDL, cirrhosis etiology, degree of alcohol consumption, encephalopathy, variceal bleeding history, or hepatocellular carcinoma between patients with or without adrenal insufficiency. Serum albumin level was lower (P < .05), and INR was higher (P < .05) in patients with than in those without adrenal insufficiency. However, multivariate analysis revealed no independent adrenal insufficiency predictor. Significant negative correlations were found between Child-Pugh score and peak cortisol levels (γ=-0.365, P = .008).Adrenal insufficiency was frequent even in hemodynamically stable patients with cirrhosis and tended to be associated with only liver disease severity, being unrelated to cirrhosis etiology.

Clotting-Factor Concentrations 5 Days After Discontinuation of Warfarin.

BACKGROUND: The American Society of Regional Anesthesia and Pain Medicine guidelines recommend discontinuation of warfarin and an international normalized ratio (INR) of 1.2 or less before a neuraxial injection. The European and Scandinavian guidelines accept an INR of 1.4 or less. We evaluated INR and levels of clotting factors (CFs) II, VII, IX, and X 5 days after discontinuation of warfarin. METHODS: Patients who discontinued warfarin for 5 days and had an INR of 1.4 or less had activities of factors II, VII, IX, and X measured. The primary outcome was the frequency of subjects with CF activities of less than 40%. RESULTS: Twenty-three patients were studied; 21 (91%) had an INR of 1.2 or less. In these 21 patients, the median (interquartile range) activities of factors II, VII, IX, and X were 66% (52%-80%), 114% (95%-132%), 101% (84%-121%), and 55% (46%-63%), respectively. Ninety-five percent (99% confidence interval, 69%-99%) had CF activities of greater than 40%. The patient who did not CF activities greater than 40% had end-stage renal disease. Two subjects had an INR of greater than 1.2; the activities of factor II, VII, IX, and X were 37% and 46%, 89% and 105%, 66% and 78%, and 20% and 36%, respectively. Neither patient had CF activities of greater than 40%. CONCLUSIONS: Based on 40% activity of CFs, patients with INRs of 1.2 or less can be considered to have adequate CFs to undergo neuraxial injections. The number of patients with an INR of 1.3 and 1.4 is too small to make conclusions.

Warfarin Safety: A Cross-Sectional Study of the Factors Associated with the Consumption of Medicinal Plants in a Brazilian Anticoagulation Clinic.

OBJECTIVE: The aim of this study was to analyze factors associated with the consumption of medicinal plants by patients being treated with warfarin in a Brazilian anticoagulation clinic and to study the safety of medicinal plant use in patients on warfarin therapy. METHODS: The study was performed as an observational cross-sectional analysis. Study participants were outpatients on long-term warfarin therapy for at least 2 months for atrial fibrillation or prosthetic cardiac valves. Interviews were carried out concerning information about the habits of medicinal herb consumption, and logistic regression analysis was performed to identify factors associated with the consumption of herbs. The scientific names of the medicinal plants were identified to search for information on the effects on the hemostasis of the interactions between the medicinal herbs reported and warfarin. RESULTS: The mean age of the 273 patients included was 60.8 years; 58.7% were women. Medicinal plants were used by 67% of the participants. No association between demographic and clinical data and the use of medicinal plants was identified. Patients reported a total of 64 different plants, primarily consumed in the form of tea. The plants were mainly used to treat respiratory tract and central nervous system disorders. About 40% of the plants cited have been reported to potentially interfere with the anticoagulation therapy, principally by potentiating the effects of warfarin, which could, increase the risk of bleeding. CONCLUSION: The use of medicinal plants was highly common and widespread in patients receiving warfarin as an anticoagulation therapy. Univariate analysis of variables associated with the consumption of herbs showed no statistically significant difference in the consumption of medicinal plants for any of the sociodemographic and clinical data. The medicinal plants that were reportedly consumed by the patients could affect hemostasis. This study reinforces the need for further studies evaluating the habits of patients consuming medicinal plants and their clinical implications, and will help to design strategies to manage the risks associated with warfarin-herbal interactions.

Comparison of Warfarin Requirements in Post-cardiac Surgery Patients: Valve Replacement Versus Non-valve Replacement.

INTRODUCTION: Anticoagulation with warfarin affects approximately 140,000 post-cardiac surgery patients every year, yet there remains limited published data in this patient population. Dosing remains highly variable due to intrinsic risk factors that plague cardiac surgery candidates and a lack of diverse literature that can be applied to those who have undergone a cardiac surgery alternative to heart valve replacement (HVR). In the present study, our aim was to compare the warfarin requirements between HVR and non-HVR patients. METHODS: This was a single-center, retrospective study of post-cardiac surgery patients initiated on warfarin at Mayo Clinic Hospital, Rochester, from January 1st, 2013 to October 31st, 2016. The primary outcome was the maintenance warfarin dose at the earliest of discharge or warfarin day 10 between patients with HVR and non-HVR cardiac surgeries. RESULTS: A total of 683 patients were assessed during the study period: 408 in the HVR group and 275 in the non-HVR group. The mean warfarin maintenance doses in the HVR and non-HVR groups were 2.55 mg [standard deviation (SD) 1.52] and 2.43 mg (SD 1.21), respectively (adjusted p = 0.65). A multivariable analysis was performed to adjust for gender, age, body mass index and drug interactions. CONCLUSIONS: This was the largest study to evaluate warfarin dose requirements in post-cardiac surgery patients and is the first to compare warfarin requirements between HVR and non-HVR patients during the immediate post-operative period. Both groups had similar warfarin requirements, which supports expanding the initial warfarin dosing recommendations of the 9th edition Chest guideline to include non-HVR patients as well as HVR patients.

Catheter ablation of left atrial arrhythmias on uninterrupted oral anticoagulation with vitamin K antagonists: What is the relationship between international normalized ratio, activated clotting time, and procedure-related complications?

BACKGROUND: Ablation of atrial fibrillation (AF) on uninterrupted phenprocoumon reduces periprocedural thromboembolic and bleeding complications. Heparin is administered intraprocedurally to achieve activated clotting times (ACT) of 300-400 seconds. We investigated the effect of international normalized ratio (INR) on ACT and intraprocedural heparin requirements. Moreover, safety of a target ACT of 250-300 seconds was investigated. METHODS AND RESULTS: We studied 949 patients referred for AF or left atrial tachycardia ablation. Patients were divided into Group 1 (n = 249) with an INR <2 and Group 2 (n = 700) with an INR ≥2. Mean INR was 1.7 ± 0.13 in Group 1 and 2.3 ± 0.25 in Group 2. Baseline, mean, minimum and maximum ACT were significantly lower in Group 1 (138 ± 17 seconds vs. 145 ± 21 seconds; 281 ± 28 seconds vs. 288 ± 29 seconds; 251 ± 36 seconds vs. 258 ± 34 seconds; 307 ± 32 seconds vs. 316 ± 40 seconds; P <0.05). Intraprocedural heparin requirements adjusted to body weight were lower in Group 1 (127 ± 41 U/kg vs. 122 ± 40 U/kg). Weak correlations between INR and baseline, mean, minimum and maximum ACT as well as intraprocedural heparin requirements were observed. No differences regarding major or minor complications were found. INR and periprocedural anticoagulation parameters had no influence on major complications. No thromboembolic complications were observed in both groups with a target ACT value of 250-300 seconds. CONCLUSIONS: There is only a weak correlation between INR, intraprocedural ACT, and intraprocedural heparin requirements. Periprocedural target ACT of 250-300 seconds seems safe and does not increase periprocedural bleeding and thromboembolic complications in patients undergoing RF ablation on uninterrupted phenprocoumon therapy.

Evaluation of the effect of torsemide on warfarin dosage requirements.

Background According to drug interaction databases, torsemide may potentiate the effects of warfarin. Evidence for this drug-drug interaction, however, is conflicting and the clinical significance is unknown. Objective The aim of this study is to evaluate the impact of torsemide initiation on warfarin dosage requirements. Setting This study was conducted at the Veterans Affairs Healthcare System in San Diego, California. Method A retrospective cohort study was conducted using Veterans Affairs data from patients who were converted from bumetanide to torsemide between March 2014 and July 2014. Patients were also prescribed and taking warfarin during the observation period. Warfarin dosage requirements were evaluated to determine if any changes occurred within the first 3 months of starting torsemide. Main outcome measure The primary outcome was the average weekly warfarin dose before and after torsemide initiation. Results Eighteen patients met study inclusion criteria. The weekly warfarin dose before and after initiation of torsemide was not significantly different (34 ± 15 and 34 ± 13 mg, p > 0.05). Of those eighteen patients, only two experienced elevations in INR that required a decrease in warfarin dosage after torsemide initiation. Between those two patients, dosage reductions ranged from 5.3 to 18%. Conclusion These results indicated that most patients did not require any warfarin dosage adjustments after torsemide was initiated. The potential for interaction, however, still exists. While empiric warfarin dosage adjustments are not recommended when initiating torsemide, increased monitoring is warranted to minimize the risk of adverse effects.

Influence of NR3C1 and VDR polymorphisms on stable warfarin dose in patients with mechanical cardiac valves.

OBJECTIVES: The aim of this study was to evaluate the associations between polymorphisms of VKORC1, CYP2C9, CYP4F2, NR3C1 and VDR genes and stable warfarin doses in Korean patients with mechanical heart valves. METHODS: Seventeen single-nucleotide polymorphisms (SNPs) in 204 patients with stable warfarin dose were analyzed: VKORC1 (rs9934438), CYP2C9 (rs1057910), CYP4F2 (rs2108622), NR3C1 (rs41423247, rs1800445, rs56149945, rs10052957, rs6198, rs33388, rs6196, and rs244465), and VDR (rs1544410, rs11568820, rs731236, rs757343, rs7975232, and rs2228570). Statistical analyses were conducted to evaluate the associations of gene variations with stable warfarin dose. Number needed to genotype was obtained by calculating the percentage of patients whose predicted dose was at least 20% higher or lower than the actual stable dose. RESULTS: The combined genotypes of rs7975232 and rs2228570 of the VDR gene revealed a significant association with stable warfarin dose, along with VKORC1, CYP2C9, and CYP4F2 polymorphisms. Patients with the genotype combination GT,TT/CT,CC of VDR rs7975232/rs2228570 required significantly higher stable warfarin dose (5.79±2.02mg) than those with the other genotypic combinations (5.19±1.78mg, p=0.034). Multivariate analysis showed that VDR rs7975232/rs2228570 explained 2.0% of the 47.5% variability in overall warfarin dose. Adding VDR SNP combinations to the base model including non-genetic variables (age, sex, and body weight) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 41. CONCLUSIONS: This study showed that stable warfarin dose is associated with VDR SNPs along with VKORC1, CYP2C9, and CYP4F2 SNPs.

Quality of warfarin therapy and risk of stroke, bleeding, and mortality among patients with atrial fibrillation: results from the nationwide FinWAF Registry.

PURPOSE: The most important management strategy in atrial fibrillation (AF) patients is preventing stroke with oral anticoagulants. Warfarin is still used as a first-line anticoagulant, although non-vitamin K antagonist oral anticoagulants are currently recommended to manage AF. Using a large, unselected national sample of AF patients, we evaluated the relationships between quality of warfarin therapy and the risks of thromboembolism, bleeding complications, and mortality. METHODS: The nationwide FinWAF study included 54 568 AF patients taking warfarin. Time in the therapeutic range (TTR) was calculated on a continuous basis using the Rosendaal method and international normalized ratio values over the previous 60 days. Adjusted Cox proportional hazard models were prepared for different TTR levels and major clinical end points. RESULTS: The mean age of patients was 73.1 years (standard deviation 10.8), and 47% were female. The mean follow-up time was 3.2 ± 1.6 years (median 3.4). In the TTR groups of ≤40%, 60-70%, 70-80%, and >80%, the annual risk of stroke was 9.3%, 4.7%, 4.6%, and 3.1%; bleeding events 7.5%, 4.5%, 4.3%, and 2.6%; and overall mortality 20.9%, 8.5%, 6.4%, and 3.1%, respectively. All differences among the TTR groups were highly significant (p < 0.001). CONCLUSIONS: The quality of warfarin treatment was strongly associated with the risk of stroke and the prognosis of AF patients. Patient outcomes continued to improve with increasing TTR values up to a TTR ≥80%; therefore, the target for the TTR should exceed 80% instead of the traditional range of at least 60-70%. Copyright © 2017 John Wiley & Sons, Ltd.

Elevated International Normalized Ratio in a Patient Taking Warfarin and Mauby: A Case Report.

We describe a 70-year-old Haitian man who had been taking warfarin for 5 years for atrial fibrillation and pulmonary hypertension. This patient had his international normalized ratio (INR) checked in the pharmacist-run anticoagulation clinic and was followed monthly. Prior to the interaction, his INR was therapeutic for 5 months while taking warfarin 10.5 mg/d. The patient presented with an INR > 8.0. Patient held 4 days of warfarin and restarted on warfarin 8.5 mg/d. Two weeks later, his INR was 2.5. After continuing dose, patient presented 2 weeks later and INR was 4.8. Upon further questioning, the patient stated he recently began ingesting mauby. Mauby is a bitter dark liquid extracted from the bark of the mauby tree that is commonly used in the Caribbean population as a folk remedy with many health benefits. This case report illustrates that mauby may have a probable drug-herb interaction (Naranjo Algorithm Score of 6) when given with warfarin. There is a lack of published literature and unclear information on the Internet describing the interaction of mauby and warfarin. Health professionals should be cautious regarding interactions between warfarin and mauby until the interaction is fully elucidated.

Endovascular stroke therapy may be safe in patients with elevated international normalized ratio.

INTRODUCTION: Endovascular therapy in acute ischemic stroke is safe and efficient. However, patients receiving oral anticoagulation were excluded in the larger trials. OBJECTIVE: To analyze the safety of endovascular therapy in patients with acute ischemic stroke and elevated international normalized ratio (INR) values. METHODS: Retrospective database review of a tertiary care university hospital for patients with anterior circulation stroke treated with endovascular therapy. Patients with anticoagulation other than vitamin K antagonists were excluded. The primary safety endpoint was defined as symptomatic intracranial hemorrhage (sICH; ECASS II definition). The efficacy endpoint was the modified Rankin scale (mRS) score after 3 months, dichotomized into favorable outcome (mRS 0-2) and unfavorable outcome (mRS 3-6). RESULTS: 435 patients were included. 90% were treated with stent retriever. 27 (6.2%) patients with an INR of 1.2-1.7 and 21 (4.8%) with an INR >1.7. 33 (7.6%) had sICH and 149 patients (34.3%) had a favorable outcome. Patients with an elevated INR did not have an increased risk for sICH or unfavorable outcome in multivariable analysis. The additional use of IV thrombolysis in patients with an INR of 1.2-1.7 did not increase the risk of sICH or unfavorable outcome. These results were replicated in a sensitivity analysis introducing an error of the INR of ±5%. They were also confirmed using other sICH definitions (Safe Implementation of Thrombolysis in Stroke (SITS), National Institute of neurological Disorders and Stroke (NINDS), Heidelberg bleeding classification). CONCLUSIONS: Endovascular therapy in patients with an elevated INR is safe and efficient. Patients with an INR of 1.2-1.7 may be treated with combined IV thrombolysis and endovascular therapy.

Poor anticoagulation relates to extended access times for cardioversion and is associated with long-term major cardiac and cerebrovascular events.

BACKGROUND: Patients undergoing elective electrical cardioversion (ECV) for atrial fibrillation have a temporarily increased risk of thromboembolism. Current guidelines recommend adequate anticoagulation for ≥3 consecutive weeks precardioversion, i.e. consecutive INR values 2.0-3.0 in patients with vitamin K antagonists (VKA). We aimed to evaluate the occurrence and impact of subtherapeutic INRs precardioversion and to study factors associated with these unwanted fluctuations. METHODS: We recruited 346 consecutive patients undergoing elective ECV in the Maastricht University Medical Centre between 2008 and 2013. Predictors of subtherapeutic INR values were identified and incorporated into a logistic regression model. RESULTS: A subtherapeutic INR precardioversion occurred in 55.2% of patients. The only statistically significant predictor was VKA-naivety (Odds Ratio (OR) 4.78, 95% Confidence Interval (CI) 2.67-8.58, p<0.001). In patients with ≥1 subtherapeutic INR precardioversion, time from referral until cardioversion was 91.1±42.8days, compared to 41.7±26.6days (p<0.001) in patients without subtherapeutic INRs. No thromboembolic events occurred <30days after the ECV. Independent predictors for the combined endpoint of cardiovascular death, ischemic stroke and the need of blood transfusion (n=30, median follow-up of 374days) were coronary artery disease in the history (OR 3.35, 95%CI 1.54-7.25, p=0.002) and subtherapeutic INR precardioversion (OR 3.64, 95%CI 1.43-9.24, p=0.007). CONCLUSIONS: The use of VKA often results in subtherapeutic INRs precardioversion and is associated with a significant delay until cardioversion, especially in patients with recent initiation of VKA therapy. Furthermore, subtherapeutic INR levels prior to ECV are associated with the combined endpoint of cardiovascular death, ischemic stroke and the need of blood transfusion.

Elevated admission international normalized ratio strongly predicts mortality in victims of abusive head trauma.

BACKGROUND: Victims of abusive head trauma have poor outcomes compared with other injured children. There is often a delay in diagnosis because these young patients are unable to communicate with health care providers. These critically injured patients would benefit from early identification and therapy. METHODS: We performed a retrospective review of our single hospital trauma registry from 2005 to 2014. All Level 1 pediatric (age 0-17 years) trauma patients who sustained abusive head trauma were included. Exclusion criteria included no admission coagulation studies, prehospital product transfusion, preexisting coagulation disorder, or death upon arrival. Primary outcome was mortality; secondary outcomes were early blood transfusion and neurosurgical intervention. Univariate analysis included Fisher's exact and Wilcoxon rank-sum testing; we then performed logistic regression modeling and calculated adjusted odds ratios (AORs) to control for known predictors of poor outcome including hypotension, hypothermia, acidosis, Injury Severity Score (ISS), and head Abbreviated Injury Scale (AIS) score. RESULTS: In 101 total subjects, 35% (n = 35) had international normalized ratio (INR) of 1.3 or greater at admission. On univariate analysis, patients with coagulation dysregulation were more likely to have hypothermia, hypotension, acidosis, high ISS, and low Glasgow Coma Scale (GCS) score (all p < 0.05). There was no difference in age, anemia, and incidence of polytrauma. Overall mortality was 24.8% (n = 25), which varied significantly based at admission INR (60% INR ≥ 1.3 vs. 6% INR > 1.3, p < 0.001). Patients with elevated INR were also more likely to have early packed red blood cell transfusion (p = 0.003) and neurosurgical intervention (p = 0.011). In logistic regression analysis, admission INR was the strongest independent predictor of mortality, with increased odds of 3.65 (p = 0.045). AOR after controlling specifically for hypotension, hypothermia, and acidosis was 6.25 (p = 0.006), and after controlling for head AIS score and admission GCS score, the AOR was 5.27 (p = 0.007). CONCLUSION: Admission INR of 1.3 or greater strongly predicts mortality in abusive head trauma. These patients should be targeted for early aggressive interventions and monitoring with the goal of improving patient outcomes. Further study is warranted to investigate potential therapeutic targets in trauma-induced coagulation dysregulation. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III.