Initial International Normalized Ratio Research Articles

Time to Peak International Normalized Ratio Rise in Acute and Acute-on-Chronic Warfarin Overdoses.

Guidelines exist on the management of supratherapeutic/subtherapeutic international normalized ratio (INR) values for patients on warfarin. However, there is a paucity of the literature relating to an acute overdose of warfarin. This is a retrospective cohort study for all acute and acute-on-chronic (AOC) warfarin overdoses reported to the Maryland Poison Center in patients ≥12 years between January 1st, 2000, until October 31st, 2019, managed in a health care facility. The primary outcome was to determine the time after presentation to peak INR. Secondary outcomes included risk factors associated with INR >10 and describing patient characteristics. A total of 163 overdoses were included, 68 acute and 95 AOC. In patients who did not receive reversal therapies, INR peaked at a median value of 3.8 (interquartile range 2.6-5.5) between 24 and 36 hours. The median time to phytonadione was 22.0 hours. Most patients received phytonadione (62.0%), with fewer receiving blood products (16.6%). The median warfarin dose ingested was 75 mg. The AOC group had a greater mean age (56 vs. 43 years), median INR value (2.4 vs. 1.4), and men (62.1% vs. 41.2%). Factors associated with an INR > 10 included initial INR and reported quantity ingested. Peak INR was greater in the AOC than the acute overdose group (6.1 vs. 3.4), although the bleeding rate was similar. Peak INR values after warfarin overdose occur between 24 and 36 hours after presentation. Initial INRs and reported quantity ingested may be useful to predict those needing treatment.

Evaluation of a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal.

Fixed-dose (FD) regimens of 4-factor prothrombin complex concentrate (4F-PCC) may be effective for the emergent reversal of warfarin; however, the optimal dosing is unknown. Our institution transitioned to a FD regimen of 1000 or 2000 units of 4F-PCC based on indication. The purpose of this study is to report our experience with FD 4F-PCC compared with a historical weight-based dosing cohort for warfarin reversal. A retrospective analysis was conducted for 3 groups: central nervous system (CNS) bleeds regardless of international normalized ratio (INR), non-CNS bleeds with an initial INR ≤6, and non-CNS bleeds with an initial INR ≥6.1. The primary outcome of the study was achievement of the target INR. There were 54 patients with a CNS bleed, 153 with a non-CNS bleed and INR ≤6, and 19 with a non-CNS bleed and INR ≥6.1. In the CNS bleeding group, weight-based and FD achieved target INR 79.4% and 70% (P = 0.52). In the INR ≥6.1 non-CNS bleeding group, weight-based and FD achieved target INR 100% and 70% (P = 0.21). In the INR ≤6 non-CNS bleeding group, weight-based and FD achieved target INR 86.4% and 57.5% (P = 0.0002). An FD strategy of 2000 units for warfarin reversal for CNS bleeds or INR ≥6.1 was comparable to weight-based dosing. The FD strategy of 1000 units for INR ≤6 achieved target INR less often than weight-based dosing. Application of findings suggest that higher doses may be needed to achieve target INR.

The outcome of three-factor Prothrombin Complex Concentrate (3F-PCC) in warfarin reversal: A single center retrospective cohort study

IntroductionThree-factor Prothrombin Complex Concentrate (3F-PCC) containing factors II, IX and X was introduced to Malaysian public hospitals for warfarin reversal since 2017. Local studies on the outcomes of 3F-PCC use are limited. ObjectiveThis study aimed to determine the extent of target international normalized ratio (INR) achievement and adverse drug reactions (ADRs) associated with 3F-PCC use in warfarin reversal. Materials and methodsThis retrospective cohort study analyzed data from adult patients on warfarin who received 3F-PCC for anticoagulation reversal between September 2017 to January 2020. Study endpoints included achievement of target INR, ADRs and in-hospital mortality. ResultsSeventy-seven patients with a median age of 65.0 (55.5–75.0) years comprising of 50.6% (n ​= ​39) men were included. Fifty-one patients required 3F-PCC for life-threatening (29.9%, n ​= ​23) and clinically significant (36.4%, n ​= ​28) bleeding. Initial INRs ranged from 1.69 to undetectable high (>24). All patients had INR reduction, of which 40.3% (n ​= ​31) achieved target INR whereas 6.5% (n ​= ​5) achieved INR below target range. Median INR reduced from 4.14 (2.89–8.13) to 1.57 (1.33–1.97). Race, gender, age, initial INR and concomitant use of adjuvant reversal therapy did not affect target INR achievement. Three (3.9%) out of four ADRs observed were associated with mortality including suspected acute coronary syndrome (n ​= ​2) and disseminated intravascular coagulopathy (n ​= ​1) among those with life-threatening bleeding. The incidence of in-hospital mortality was 19.5% (n ​= ​15). ConclusionThe use of 3F-PCC (Prothrombinex-VF®) produces variable reduction in INR in our population without apparent risk of thromboembolic events and in-hospital mortality.

Propensity score adjusted comparison of three-factor versus four-factor prothrombin complex concentrate for emergent warfarin reversal: a retrospective cohort study

BackgroundProthrombin Complex Concentrates (PCC) are prescribed for emergent warfarin reversal (EWR). The comparative effectiveness and safety among PCC products are not fully understood.MethodsPatients in an academic level one trauma center who received PCC3 or PCC4 for EWR were identified. Patient characteristics, PCC dose and time of dose, pre- and post-INR and time of measurement, fresh frozen plasma and vitamin K doses, and patient outcomes were collected. Patients whose pre-PCC International Normalized Ratio (INR) was > 6 h before PCC dose or the pre-post PCC INR was > 12 h were excluded. The primary outcome was achieving an INR ≤ 1.5 post PCC. Secondary outcomes were the change in INR over time, post PCC INR, thromboembolic events (TE), and death during hospital stay. Logistic regression modelled the primary outcome with and without a propensity score adjustment accounting for age, sex, actual body weight, dose, initial INR value, and time between INR measurements. Data are reported as median (IQR) or n (%) with p < 0.05 considered significant.ResultsEighty patients were included (PCC3 = 57, PCC4 = 23). More PCC4 patients achieved goal INR (87.0% vs. 31.6%, odds ratio (OR) = 14.4, 95% CI: 3.80–54.93, p < 0.001). This result remained true after adjusting for possible confounders (AOR = 10.7, 95% CI: 2.17–51.24, p < 0.001). The post-PCC INR was lower in the PCC4 group (1.3 (1.3–1.5) vs. 1.7 (1.5–2.0)). The INR change was greater for PCC4 (2.3 (1.3–3.3) vs. 1.1 (0.6–2.0), p = 0.003). Death during hospital stay (p = 0.52) and TE (p = 1.00) were not significantly different.ConclusionsPCC4 was associated with a higher achievement of goal INR than PCC3. This relationship was observed in the unadjusted and propensity score adjusted results.

A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study

BackgroundVitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables.ObjectiveThe authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patientsMethodologyDNA was obtained from 304 patients as a discovery cohort with an international normalized ratio (INR) range of 2.0–3.0. The non-genetic (demographic and clinical) variables were also recorded. Genotype analyses were performed using real-time PCR for VKORC1 (rs9923231), VKORC1 (rs7294), GGCx (rs11676382), CYP4F2 (rs2108622), ABCB1 (rs1045642), CYP2C9*2 (rs1799853), ApoE (rs429358), and CYP2C9*3 (rs1057910).ResultsThe clinical variables that significantly influenced the weekly therapeutic dose of VKA were age, sex, body mass index (BMI), and initial INR, collectively accounting for 19% of the variability, and the genetic variables with a significant impact were VKORC1 (rs9923231), CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910), explaining for another 37% of the variability.ConclusionWe developed an algorithm that explains 49.99% of the variability in therapeutic VKA dosage in the Chilean population studied. Factors that significantly affected the dosage included VKORC1, CYP2C9*2, and CYP2C9*3 polymorphisms, as well as age, sex, BMI, and initial INR.

A Machine Learning-Based Model to Predict Acute Traumatic Coagulopathy in Trauma Patients Upon Emergency Hospitalization.

Acute traumatic coagulopathy (ATC) is an extremely common but silent murderer; this condition presents early after trauma and impacts approximately 30% of severely injured patients who are admitted to emergency departments (EDs). Given that conventional coagulation indicators usually require more than 1 hour after admission to yield results—a limitation that frequently prevents the ability for clinicians to make appropriate interventions during the optimal therapeutic window—it is clearly of vital importance to develop prediction models that can rapidly identify ATC; such models would also facilitate ancillary resource management and clinical decision support. Using the critical care Emergency Rescue Database and further collected data in ED, a total of 1385 patients were analyzed and cases with initial international normalized ratio (INR) values >1.5 upon admission to the ED met the defined diagnostic criteria for ATC; nontraumatic conditions with potentially disordered coagulation systems were excluded. A total of 818 individuals were collected from Emergency Rescue Database as derivation cohorts, then were split 7:3 into training and test data sets. A Pearson correlation matrix was used to initially identify likely key clinical features associated with ATC, and analysis of data distributions was undertaken prior to the selection of suitable modeling tools. Both machine learning (random forest) and traditional logistic regression were deployed for prediction modeling of ATC. After the model was built, another 587 patients were further collected in ED as validation cohorts. The ATC prediction models incorporated red blood cell count, Shock Index, base excess, lactate, diastolic blood pressure, and potential of hydrogen. Of 818 trauma patients filtered from the database, 747 (91.3%) patients did not present ATC (INR ≤ 1.5) and 71 (8.7%) patients had ATC (INR > 1.5) upon admission to the ED. Compared to the logistic regression model, the model based on the random forest algorithm showed better accuracy (94.0%, 95% confidence interval [CI]: 0.922-0.954 to 93.5%, 95% CI: 0.916-0.95), precision (93.3%, 95% CI: 0.914-0.948 to 93.1%, 95% CI: 0.912-0.946), F1 score (93.4%, 95% CI: 0.915-0.949 to 92%, 95% CI: 0.9-0.937), and recall score (94.0%, 95% CI: 0.922-0.954 to 93.5%, 95% CI: 0.916-0.95) but yielded lower area under the receiver operating characteristic curve (AU-ROC) (0.810, 95% CI: 0.673-0.918 to 0.849, 95% CI: 0.732-0.944) for predicting ATC in the trauma patients. The result is similar in the validation cohort. The values for classification accuracy, precision, F1 score, and recall score of random forest model were 0.916, 0.907, 0.901, and 0.917, while the AU-ROC was 0.830. The values for classification accuracy, precision, F1 score, and recall score of logistic regression model were 0.905, 0.887, 0.883, and 0.905, while the AU-ROC was 0.858. We developed and validated a prediction model based on objective and rapidly accessible clinical data that very confidently identify trauma patients at risk for ATC upon their arrival to the ED. Beyond highlighting the value of ED initial laboratory tests and vital signs when used in combination with data analysis and modeling, our study illustrates a practical method that should greatly facilitates both warning and guided target intervention for ATC.

Modified version of the American College of Cardiology's recommendation for low-dose prothrombin complex concentrate is effective for warfarin reversal

BackgroundDosing of four factor prothrombin complex concentrate (4PCC) for warfarin reversal remains controversial. Recently, the American College of Cardiology (ACC) recommended a low-dose PCC regimen as an option for warfarin reversal in acute major bleeding. We performed a retrospective study evaluating if a modified version of the ACC guideline recommendations was effective for warfarin reversal in acute major bleeds when compared to traditional variable dosing. MethodsThis was a retrospective cohort study of patients who received 4PCC for warfarin reversal in a 12 month period. We included patients that were ≥18 years of age, received 4PCC for warfarin reversal, and had an initial International Normalized Ratio (INR) of >2. Our primary outcome was the number of patients who had a post-4PCC infusion INR of <1.6. ResultsA total of 60 patients were included in the final analysis with 30 patients stratified to the traditional dosing and low-dose groups, respectively. Patient demographics were similar between both groups. We found no difference in the number of patients who had a post-4PCC infusion INR <1.6 between the traditional dosing and low dosing group (90.0% vs. 86.7%; p = 0.68). Additionally, we found no difference between post-infusion median INRs in each group (1.35 vs. 1.30; p = 0.16). Approximately 1000 units per patient were spared when utilizing the low-dose regimen. ConclusionA modified version of the ACC's low-dose 4PCC option for warfarin reversal achieves similar outcomes for lowering INR values compared to traditional variable dosing regimens.

A Simple Formula for Predicting the Maintenance Dose of Warfarin with Reference to the Initial Response to Low Dosing at an Outpatient Clinic

Objective The pharmacodynamic effect of warfarin varies among individuals, and its maintenance dose is widely distributed. Although many formulae for predicting the maintenance dose of warfarin have been developed, most of them are complex and not in practical use. Methods and Materials Among 12,738 new patients visiting the Cardiovascular Institute between 2004 and 2009, we identified 127 patients (66.6±8.8 years, 89 men) with atrial fibrillation for whom warfarin was newly started with an initial dose of 2 mg/day and the international normalized ratio (INR) at 1 year after warfarin was started was within the therapeutic range. The prediction models for the maintenance dose were developed by an exponential equation and a first-order equation. Results The initial response of the INR to the dose of 2 mg/day (initial INR) ranged from 1.00-3.24 (mean 1.43), while the maintenance dose of warfarin ranged from 0.5-14 mg (mean 3.8 mg). The maintenance dose showed an exponential correlation to the initial INR: (predicted maintenance dose) =5.522× (initial INR)−1.556 (R2=0.795, p<0.001). Excluding the patients with a poor response to the initial dose (initial INR <1.1, n=32) permitted a simple correlation with a first-order approximation: (predicted maintenance dose) =−2.009× (initial INR) +6.172 (R2=0.706, p<0.001). Conclusion We developed a simple formula for predicting the maintenance dose of warfarin using the initial response of the INR to low-dose warfarin.

Anticoagulation management by physician-clinical pharmacist team for patients with valvular atrial fibrillation

Objective To evaluate the effectiveness of anticoagulation management by physician-clinical pharmacist team for patients with valvular atrial fibrillation. Methods One hundred and seventy two patients with valvular atrial fibrillation received warfarin therapy for anticoagulation during hospitalization in Linyi People′s Hospital from January 2014 to December 2016, the patients continued to receive warfarin therapy for>6 months after discharge. The patients were randomly assigned in two groups: the anticoagulation management was given by physician-clinical pharmacist team in 87 cases (trial group), while the dosage of wargarin was adjusted in outpatient department by physicians alone in 85 cases (control group). The goal attainment rate of international normalized ratio (INR), the proportion of patients with a stable warfarin dose, knowledge of anticoagulants, belief of medication, medication compliance were compared between two groups. Results There were no significant differences in age, sex, body weight, smoking and drinking habits, valvular disease type, comorbidities; and the initial INR, knowledge of anticoagulants, belief of medication and medication compliance at admission between two groups (all P>0.05). The goal attainment rate of INR (52.17% vs. 41.02%, χ2=8.178,P=0.004), the proportion of patients with a stable dose of warfarin (74.71% vs. 56.47%, χ2=6.349, P=0.012), the knowledge of anticoagulants(11.03±2.25 vs. 10.08±1.86, t=3.018, P=0.003), the belief of medication[(12.23±2.07) vs.(11.67±1.48), t=2.042, P=0.043], and the medication compliance[(7.36±0.89) vs. (7.04±1.10), t=2.112 8, P=0.036] in the trial group were significantly higher than those in control group. Conclusion Anticoagulation management by physician-clinical pharmacist team can improve the management level of anticoagulation and the knowledge of anticoagulans, enhance the medication belief, improve the goal attainment rate of INR and the compliance rate of medication in patients with valvular atrial fibrillation. Key words: Atrial fibrillation; Warfarin; Anticoagulation management service; Physician; Clinical pharmacist; International normalized ratio

The role of four-factor prothrombin complex concentrate in coagulopathy of trauma: A propensity matched analysis.

Coagulopathy is a common complication after severe trauma. The efficacy of 4-factor prothrombin complex concentrate (4-PCC) as an adjunct to fresh frozen plasma (FFP) in reversal of coagulopathy of trauma (COT) has not been studied. The aim of our study is to compare 4-PCC + FFP versus FFP alone for the treatment of COT. We reviewed all trauma patients older than 18 years who received PCC + FFP or FFP alone at our Level I trauma center from 2015 to 2016. We excluded patients on preinjury oral anticoagulants. Patients were divided into two groups (4-PCC + FFP: FFP alone) and were matched in a 1:2 ratio using propensity score matching for demographics, vital and injury parameters, and initial international normalized ratio (INR). COT was defined as admission INR > 1.5. Corrected INR was defined as an INR of 1.5 or less. Outcome measures were time to correction of INR, packed red blood cells units transfused, thromboembolic complications, and mortality. We analyzed 516 trauma patients, of which 120 patients (4-PCC + FFP: 40, FFP: 80) were matched. Mean age was 58 ± 20 years; 60% were male, median Injury Severity Score was 29 (14-38). Mechanism of injury was blunt in 87% patients. 4-PCC + FFP was associated with an accelerated correction of INR (373 minutes vs. 955 minutes; p = 0.001), a decrease in packed red blood cells units (7 units vs. 9 units; p = 0.04), and FFP units (5 units vs. 7 units; p = 0.03) transfused compared to FFP alone. 4-PCC + FFP was associated with a lower mortality (25% vs. 33% p = 0.04) compared with FFP alone; however, there was no difference in the thromboembolic complications (2.5% vs. 1.2%, p = 0.5) between the two groups. Administration of PCC + FFP led to an earlier correction of the INR compared with FFP alone. Results of our study demonstrated that the use of 4-PCC in conjunction with FFP is associated with the rapid reversal of INR and reduction in transfusion requirements as compared with FFP alone. Four-factor PCC as a component therapy along with FFP is superior to FFP alone for the reversal of COT. Therapeutic studies, level IV.

Use of three procoagulants in improving bleeding outcomes in the warfarin patient with intracranial hemorrhage

: When patients on anticoagulation present with intracranial bleeding, stopping the bleeding is paramount. Despite the availability of multiple options to reverse anticoagulation, no study has directly compared the effectiveness of the procoagulants recombinant activated factor VII (rFVIIa), the rFVIIa and 3-factor prothrombin complex concentrate (PCC) combination, and 4-factor PCC on improving patient outcomes compared with a control. This study examined the medical records of 197 warfarin patients with intracranial hemorrhage, an initial international normalized ratio (INR) greater than 1.5, and who received rFVIIa (26), the combination (84), 4-PCC (50), or no procoagulant, the control group (37). Mortality, length of stay, location discharged, change in INR prior to and postdrug administration, plasma use, and number of thromboembolic complications were used to assess effectiveness. Although INR decreased in all groups (1.31 rFVIIa vs. 2.04 combination vs. 1.41 4-PCC vs. 1.20 control, P = 0.07), the combination group had the greatest percentage to reach an INR of less than 1.3 (46.2 vs. 73.8 vs. 58.0 vs. 43.2%, P = 0.004). The combination and control groups experienced a high, though nonsignificant, number of thromboembolic complications (5.6 vs. 19.0 vs. 7.7 vs. 12.9%, P = 0.533). The rFVIIa group used the most plasma and had the longest length of stay. Mortality did not differ significantly among groups. Although the combination improved INR compared with control, this had a high number of complications. Judicious use of procoagulants is recommended due to their expense and lack of significant improvement in outcomes compared with control.

Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage

BackgroundPatients with traumatic intracranial hemorrhage (TIH) anticoagulated with warfarin are at an increased risk of mortality. Fresh frozen plasma (FFP) and vitamin K have been the standard treatment for warfarin reversal; however, guidelines now recommend the use of prothrombin complex concentrate (PCC) for warfarin reversal in patients with life-threatening bleeding. Our protocol uses one vial (∼1000 units) of activated PCC (aPCC) for warfarin reversal, regardless of the weight or presenting international normalized ratio (INR). The purpose of this study was to determine the safety and efficacy of using fixed, low-dose aPCC for warfarin reversal in patients with TIH. MethodsThis was a retrospective chart review that included patients with an Abbreviated Injury Scale Head score of ≥3, TIH, and initial INR ≥ 1.5 on warfarin. Patients aged <18 years and those with no repeat INR were excluded. The primary outcome was to compare the percentage of patients with INR ≤ 1.4 after receiving aPCC versus FFP within 24 hours. ResultsEighty-nine patients were in the FFP group and 31 patients in the aPCC group. The INR was reversed more effectively in the aPCC group compared with the FFP group (90.3% versus 69.7%, P = 0.029). The median time (hours) to reversal was also significantly shorter in the aPCC group compared with the FFP group (3.75 versus 6.75, P = 0.003). However, there was no difference in mortality (35.5% aPCC versus 22.2% control, P = 0.162) or incidences of thrombosis. ConclusionFixed, low-dose aPCC is safe and more effective at reversing the effects of warfarin than FFP in patients with TIH.

The Effect of Time to International Normalized Ratio Reversal on Intracranial Hemorrhage Evolution in Patients With Traumatic Brain Injury.

The incidence of geriatric traumatic brain injury (TBI) is increasing throughout the United States, with many of these patients taking anticoagulation (AC) medication. The purpose of this investigation was to determine the effect of time to international normalized ratio (INR) reversal on intracranial hemorrhage evolution in TBI patients taking prehospital AC medication. We hypothesized that rapid reversal of INR improves outcomes of head-injured patients taking AC medication. Admissions to a Level II trauma center between February 2011 and December 2013 were reviewed. Patients presenting with an initial INR of 2.0 or more, computed tomographic scan positive for intracranial hemorrhage, and INR reversal to less than 1.5 in hospital were included. Patients with nontraumatic intracranial hemorrhage were excluded. Reversal of INR was achieved using some combination of fresh frozen plasma, prothrombin complex concentrate, and vitamin K. A binary logistic regression model assessed the adjusted impact of rapid INR reversal on intracranial hemorrhage evolution. Significance was defined as p < .05. One hundred subjects were included. Four patients with nontraumatic intracranial hemorrhage were excluded, resulting in a final study population of 96 patients. The most common intracranial hemorrhage in the study population was subarachnoid hemorrhage (71.9%), followed by subdural hemorrhage (35.4%). Reversal of INR of less than 5 hr was not associated with intracranial hemorrhage evolution; however, reversal of less than 10 hr was found to be associated with a decreased odds ratio for intracranial hemorrhage evolution (p = .043). Rapid reversal of elevated INR levels (<10 hr) may decrease intracranial hemorrhage evolution in TBI patients taking prehospital AC medication.

Plasma Transfusion Demystified: A Review of the Key Factors Influencing the Response to Plasma Transfusion.

Many studies have suggested that inappropriate plasma usage is common. An important factor contributing to futile plasma administration in most patients is the nonlinear relationship between coagulation-factor levels and the volume of plasma transfused. In this review, a validated mathematical model and data from the literature will be used to illuminate 3 key properties of plasma transfusion. Those properties are as follows: the effect of plasma transfusion on international normalized ratio (INR) is transient; for the same volume of transfused plasma, a greater reduction in INR is observed at higher initial INRs; and the effect of plasma transfusion on INR correction (ie, the difference between initial and final INRs) diminishes as more plasma is transfused. Frequent misunderstanding of these properties may contribute to inappropriate plasma usage. Therefore, this review will assist physicians in navigating these common pitfalls. Stronger understanding of these principles may result in a reduction of inappropriate plasma transfusions, thus potentially enhancing patient safety and reducing healthcare costs.

AHEAD Study: an observational study of the management of anticoagulated patients who suffer head injury

ObjectivesManagement of anticoagulated patients after head injury is unclear due to lack of robust evidence. This study aimed to determine the adverse outcome rate in these patients and identify risk...

Fibrinogen is an independent predictor of mortality in major trauma patients: A five-year statewide cohort study

IntroductionFibrinogen may be reduced following traumatic injury due to loss from haemorrhage, increased consumption and reduced synthesis. In the absence of clinical trials, guidelines for fibrinogen replacement are based on expert opinion and vary internationally. We aimed to determine prevalence and predictors of low fibrinogen on admission in major trauma patients and investigate association of fibrinogen levels with patient outcomes. Patients and methodsData on all major trauma patients (January 2007–July 2011) identified through a prospective statewide trauma registry in Victoria, Australia were linked with laboratory and transfusion data. Major trauma included any of the following: death after injury, injury severity score (ISS) >15, admission to intensive care unit requiring mechanical ventilation, or urgent surgery for intrathoracic, intracranial, intra-abdominal procedures or fixation of pelvic or spinal fractures. Associations between initial fibrinogen level and in-hospital mortality were analysed using multiple logistic regression. ResultsOf 4773 patients identified, 114 (2.4%) had fibrinogen less than 1g/L, 283 (5.9%) 1.0–1.5g/L, 617 (12.9%) 1.6–1.9g/L, 3024 (63.4%) 2–4g/L and 735 (15%) >4g/L. Median fibrinogen was 2.6g/L (interquartile range 2.1–3.4). After adjusting for age, gender, ISS, injury type, pH, temperature, Glasgow Coma Score (GCS), initial international normalised ratio and platelet count, the lowest fibrinogen categories, compared with normal range, were associated with increased in-hospital mortality (adjusted odds ratio [OR] for less than 1g/L 3.28 [95% CI 1.71–6.28, p<0.01], 1–1.5g/L adjusted OR 2.08 [95% CI 1.36–3.16, p<0.01] and 1.6–1.9g/L adjusted OR 1.39 [95% CI 0.97–2.00, p=0.08]). Predictors of initial fibrinogen <1.5g/L were younger age, lower GCS, systolic blood pressure <90mmHg, chest decompression, penetrating injury, ISS >25 and lower pH and temperature. ConclusionsInitial fibrinogen levels less than the normal range are independently associated with higher in-hospital mortality in major trauma patients. Future studies are warranted to investigate whether earlier and/or greater fibrinogen replacement improves clinical outcomes.

Should We Use Bridging Therapy during Switching Patients from Warfarin to Novel Oral Anticoagulants?

Rivaroxaban is a new anticoagulant that was approved by the Food and Drug Administration in 2011 for stroke and systemic embolism prophylaxis in patients with nonvalvular atrial fibrillation. Several characteristics have made rivaroxaban an attractive alternative to warfarin: once-daily dosing, obviating the need for monitoring the international normalized ratio (INR), noninferiority to warfarin for preventing stroke in patients with atrial fibrillation, and comparatively lower risk of intracranial hemorrhage. Both The European Summary of Product Characteristics and the US Prescribing Information recommend to discontinue warfarin and to start rivaroxaban on the following day if the initial INR level is below 3.0, yet many clinics convert patient from warfarin to rivaroxaban when INR level is <2.0 due to increased risk of hemorrhage. Since there are no conventional coagulation measures to reliably demonstrate the level of anticoagulation in patients on rivaroxaban, there is an increased risk of adverse events, especially for patients with high ischemic burden. We report a case of acute ischemic stroke in a patient who switched from warfarin to rivaroxaban (20 mg once daily). A 68-year-old female patient with multiple co-morbidities was admitted to our clinic with ischemic stroke. After 1 week follow-up with parenteral anticoagulation in the neurology clinic, she was discharged with mild deficits and with dabigatran treatment (150 mg twice daily). Novel oral anticoagulants are attractive options for anticoagulation particularly in patients who are incompatible with warfarin therapy. On the other hand, physicians should be alert during switching patients from warfarin to novel oral anticoagulants.

A multi-factorial analysis of response to warfarin in a UK prospective cohort.

BackgroundWarfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin.MethodsA prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R.ResultsVKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role.ConclusionOur multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0255-y) contains supplementary material, which is available to authorized users.

A new kid on the block: Outcomes with Kcentra 1 year after approval.

As the population ages, more trauma patients are admitted with coagulopathy. Fresh frozen plasma is effective in reversing coagulopathy caused by warfarin; however, it is not appropriate for all patients. Prothrombin complex concentrates (PCCs) are an alternative for patients who require emergent reversal, minimal-volume administration and who have a supratherapeutic international normalized ratio (INR). A four-factor PCC initially approved in Europe is now available in the United States. We sought to review our experience with Kcentra (4F-PCC) in the first year following Food and Drug Administration approval. All trauma patients admitted to an academic Level 1 trauma center between July 15, 2013, and July 15, 2014, who received 4F-PCC for reversal of warfarin-induced coagulopathy were reviewed. 4F-PCC was given as per protocol. Univariate analysis was performed to examine patient demographics, injury characteristics, coagulation studies, 4F-PCC dose, vitamin K use, transfusions, response to reversal, duration of reversal, complications, and mortality. Twenty-six patients met study criteria. Of these patients, 34.6% were reversed because of intracranial hemorrhage. The mean INR decreased from 5.7 ± 6.1 (range, 1.6-30) to 1.5 ± 0.4 (range, 1.2-2.6) after 4F-PCC administration. One patient (3.8%) received concurrent fresh frozen plasma. For patients with an initial INR greater than 5.0, the mean INR decreased from 12.0 ± 8.2 to 1.6 ± 0.5. Forty-eight hours following 4F-PCC administration, mean INR for all patients remained 1.4 ± 0.4 (range, 1.0-2.6). Of the patients, 80.8% received vitamin K over this period. Fourteen patients had a pre-4F-PCC thromboelastogram; four were hypocoagulable. Two patients had repeat thromboelastograms after 4F-PCC was given, which demonstrated normal coagulation. Of the patients with intracranial hemorrhage, 66.7% showed radiographic progression of the initial insult on post-4F-PCC head computed tomography, while only 11.1% progressed clinically. In-hospital mortality was 0%. There were no thromboembolic complications. 4F-PCC effectively reverses elevated INRs in trauma patients with warfarin-induced coagulopathy, with results lasting more than 48 hours after administration. Therapeutic study, level V.

Influence of CYP2C9 polymorphism on the fall in International Normalized Ratio in patients interrupting warfarin therapy before elective surgery

Patients on warfarin are normally required to stop treatment for a fixed number of days prior to an invasive procedure. However, the anticoagulant activity of warfarin subsides at different rates among different patients. The aim of this study was to investigate the potential influence of CYP2C9 polymorphism on the variable rate of fall in the International Normalized Ratio (INR) in patients withdrawing from warfarin treatment prior to elective surgery. One hundred and fifty-two patients aged 43-93years were recruited. Demographic data on age, height, weight, gender, daily warfarin dose, indication for anticoagulation therapy, medical diagnosis, surgical operation planned and concomitant medication were recorded. A blood sample was taken for later CYP2C9 genotyping. For patients with two CYP2C9 variant alleles (CYP2C9*2*2 or CYP2C9*2*3), the odds of having an INR of ≥1.5 before the planned day of surgery were 8.64 times greater (95% confidence interval [CI]2.25-33.25) than for other patients. Multiple regression analysis revealed that the rate of fall in the INR was reduced in the presence of two CYP2C9 variant alleles, as well as increasing patient age, weight and number of comorbidities, and increased with increasing initial INR (F5,132 =242.9, P<0.0001), all of which accounted for ~90% of the interindividual variability in the fall in INR. A genotype-guided protocol to tailor warfarin withdrawal according to an individual patient's CYP2C9 genotype could reduce cancellation or delays of planned procedures, and could also be beneficial when transitioning patients from warfarin to one of the new oral anticoagulants.