International Normalized Ratio Correction Research Articles

Correction of Warfarin Coagulopathy for Non-bleeding Patients in the Outpatient Setting at an Ambulatory Care Organization: Application of Vitamin K Guidance

Background: Warfarin is an effective anticoagulant but requires close International Normalized Ratio (INR) monitoring and may occasionally require correction of excessive anticoagulation. Current guidelines provide limited practical guidance on the administration of vitamin K for the management of supratherapeutic INR levels ≥ 5.0 in non-bleeding outpatients. Objective: Based on expert consensus and guidelines, the Atrius Health Anticoagulation Management Services (AMS) has developed internal guidance for oral vitamin K use in highly selected populations. This study will describe the internal guidance for oral vitamin K use and present associated results and clinical outcomes Methods: Episodes with INR > 5.0 were included, with vitamin K considered for episodes with INR ≥ 6. Moreover, compelling indications and exclusions to select ideal patients for vitamin K intervention were also defined Results: Overall, episodes were managed conservatively; of the 246 collected episodes of excessive anticoagulation, in 18 episodes (7%), patients received vitamin K, and in 228 (93%) episodes, patients did not receive vitamin K. The mean index INR was 6.0 (range 5.0 – 10.5, SD 1.07), with nearly 57% of episodes achieving INR correction and 15% of episodes developing INR overcorrection. High thrombotic risk patients, regardless of hemorrhagic risk, were less likely to receive vitamin K. Three episodes (1.2%) resulted in bleeding complications. No thrombotic complications occurred during the 30-day follow-up of the index INR value ≥ 5.0. Conclusion: Our internal guidance is a novel, standardized approach that serves as a decision support tool for the management of warfarin-associated coagulopathy and vitamin K intervention using patient-specific characteristics and index INR values. This guidance may assist other anticoagulation management services with practical applications and require validation in a prospective clinical trial.

A Phase 3, Prospective, Randomized, Double-Blind, Multicenter, Non-Inferiority Study Comparing Two Four-Factor Prothrombin Complex Concentrates for Reversal of Vitamin K Antagonist-Induced Anticoagulation in Patients Needing Urgent Surgery with Significant Bleeding Risk

Introduction: The 4-factor prothrombin complex concentrates (4F-PCCs) are very effective in urgent reversal of vitamin K antagonist (VKA) anticoagulant therapy, including correction of the International Normalized Ratio (INR). This study (LEX-209) compared the hemostatic efficacy of an investigational 4F-PCC (Octaplex®; Octapharma) with a control 4F-PCC (Beriplex® P/N, also known as Kcentra®; CSL Behring). Methods: Patients included were ≥18 years old, on VKA therapy, hospitalized for urgent surgery with a significant bleeding risk (≥50 mL) for which VKA withdrawal and intravenous vitamin K were considered to be insufficient, and had an INR ≥2.0. Patients received a single intravenous 4F-PCC dose of 25, 35, or 50 international units (IU)/kg body weight per baseline INR (2-<4, 4-6, >6, respectively); infusion rate was 0.12 mL/kg/min (~3 IU/kg/min) up to 8.4 mL/min (~210 IU/min). The primary endpoint was hemostatic efficacy rating at surgery end assessed by a blinded Independent Endpoint Adjudication Board using establised objective criteria. Secondary efficacy endpoints were the proportion of patients with INR ≤1.5, and changes in coagulation factor levels (FII, FVII, FIX, FX), at 30 (±15) minutes post-infusion. Safety endpoints included treatment-emergent adverse events (TEAEs), and thromboembolic events (TEEs) and mortality at 3, 21, and 45 days post-surgery. The Farrington-Manning test was used to assess the primary hypothesis that investigational 4F-PCC was non-inferior to control 4F-PCC (80% power, 15% non-inferiority margin). A pre-planned interim analysis was performed on the first 50% of randomized patients (≥185 patients). Results: This Phase 3 study was performed at 24 sites in the USA and Europe from June 2017-November 2021 and randomized 208 patients to investigational 4F-PCC (N=105) or control 4F-PCC (N=103). Baseline characteristics with respect to age, sex, and baseline INR for patients included in the two groups were similar, and the most common location of the planned surgery was gastrointestinal. The pre-procedural estimated maximum blood loss ≥200 mL was also similar in both groups (67.6% vs. 67.0% patients, respectively). Median dose was 25 IU/kg in both groups (range: 16-50 IU/kg investigational 4F-PCC, 15-50 IU/kg control 4F-PCC). Median (range) duration of infusion was 12 (8-50) minutes and 13 (7-30) minutes, respectively. The primary objective was met at the interim analysis and the study was stopped for non-inferiority. In the final analysis, investigational 4F-PCC was non-inferior to the control 4F-PCC, with effective hemostasis at surgery end achieved in 94.3% vs. 94.2% patients (Table 1). The proportion of patients achieving INR ≤1.5 was 78.1% with investigational 4F-PCC vs. 71.8% with control 4F-PCC (proportion difference 0.063; 95% confidence interval [CI] −0.056, 0.181; Figure 1). No patient had surgery cancelled for inadequate INR correction. Mean activities of coagulation factors (FII, FVII, FIX, FX) similarly increased in both groups. Similar proportions of patients in the investigational and control 4F-PCC groups experienced TEAEs (81.9% vs. 77.7%) and drug-related TEAEs (both 1.0%). The most common adverse reactions observed in patients who received investigational 4F-PCC were asthenia, anemia, and catheter site related reaction. One death occurred <21 days post-surgery, in the control 4F-PCC group, which was considered unrelated to the product by the investigator. Two TEEs occurred <21 days post-surgery in the investigational 4F-PCC group (unstable angina on day 5, reported as possibly related). Conclusions: The investigational 4F-PCC was non-inferior to control 4F-PCC for reversal of VKA in patients undergoing urgent surgery with significant bleeding risk. INR reductions and coagulation factor increases supported the primary endpoint. The safety profile was similar between treatment arms and consistent with previous studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Vitamin K antagonist reversal strategies: Systematic review and network meta‐analysis from the AABB

Anticoagulation requires urgent reversal in cases of life-threatening bleeding or invasive procedures. Network meta-analysis for comparing the safety and efficacy of warfarin reversal strategies including plasma and prothrombin complex concentrates (PCCs). Seven studies including 594 subjects using reversal agents plasma, 3-factor-PCC (Uman Complex and Konyne), and 4-factor-PCC (Beriplex/KCentra, Octaplex, and Cofact) met inclusion criteria. Compared with plasma, patients receiving Cofact probably have a higher rate of international normalized ratio (INR) correction (risk difference [RD] 499 more per 1000 patients, 95% confidence interval [CI], 176-761, low certainty[LC]); higher reversal of bleeding (323 more per 1000 patients, 11-344 more, LC); and fewer transfusion requirements (0.96 fewer units, 1.65-0.27 fewer, LC). Patients receiving Beriplex/KCentra probably have a higher rate of INR correction (476 more per 1000 patients, 332-609 more, LC); higher reversal of bleeding (127 more per 1000 patients, 43 fewer to 236 more); and similar transfusion requirements (0.01 fewer units, 0.31 fewer to 0.28 more, high/moderate certainty). Patients receiving Octaplex probably have a higher rate of INR correction (RD 579 more per 1000 patients, 189-825 more, LC). PCCs probably provide an advantage in INR reversal compared to plasma. There was no added risk of adverse events with PCCs.

High versus low fixed-dose four factor-prothrombin complex concentrate for warfarin reversal in patients with intracranial hemorrhage

BackgroundFour-factor prothrombin complex concentrate 4F-PCC is the standard of care for warfarin reversal in patients with major bleed or requiring urgent surgery. Although the 4F-PCC dose is weight and international normalized ratio (INR) based, for practical purposes, a fixed-dose approach has been explored, especially for rapid reversal. We report our experience using two different fixed-dose 4F-PCC for warfarin reversal in patients presenting with intracranial hemorrhage (ICH). Study design and methodsWe completed a retrospective chart review comparing high (4000 units) versus low (2000 units) dose 4F-PCC by evaluating patient characteristics, laboratory data, and pre-and post-4F-PCC brain imaging. ResultsThere was no significant difference between patient characteristics or INR correction (≤1.5) between the two groups. Eighty percent (12/15) of patients who received the low dose 4F-PCC had either improved or stable brain imaging as compared to 88% (14/16) of patients who received the high dose PCC. When the eight patients (4 from each arm of the study) who required neurosurgery were excluded, only two patients in each arm had worse imaging after 4F-PCC. ConclusionThere was no significant difference between the INR correction and the brain imaging changes in patients with an ICH who received either the high or the low fixed-dose 4F-PCC for warfarin reversal.

Prothrombin Complex Concentrate for Trauma Induced Coagulopathy: A Systematic Review and Meta-Analysis.

Optimal management for trauma-induced coagulopathy (TIC) is a clinical conundrum. In conjunction with the transfusion of fresh-frozen plasma (FFP), additional administration of prothrombin complex concentrate (PCC) was proposed to bring about further coagulative benefit. However, investigations evaluating the efficacy as well as corresponding side effects were scarce and inconsistent. The aim of this study was to systematically review current literature and to perform a meta-analysis comparing FFP+PCC with FFP alone. Web search followed by manual interrogation was performed to identify relevant literatures fulfilling the following criteria, subjects as TIC patients taking no baseline anticoagulants, without underlying coagulative disorders, and reported clinical consequences. Those comparing FFP alone with PCC alone were excluded. Comprehensive Meta-analysis software was utilized, and statistical results were delineated with odd ratio (OR), mean difference (MD), and 95% confidence interval (CI). I2 was calculated to determine heterogeneity. The primary endpoint was set as all-cause mortality, while the secondary endpoint consisted of international normalized ratio (INR) correction, transfusion of blood product, and thrombosis rate. One hundred and sixty-four articles were included for preliminary evaluation, 3 of which were qualified for meta-analysis. A total of 840 subjects were pooled for assessment. Minimal heterogeneity was present in the comparisons (I2 < 25%). In the PCC + FFP cohort, reduced mortality rate was observed (OR: 0.631; 95% CI: 0.450-0.884, p = 0.007) after pooling. Meanwhile, INR correction time was shorter under PCC + FFP (MD: -608.300 mins, p < 0.001), whilst the rate showed no difference (p = 0.230). The PCC + FFP group is less likely to mandate transfusion of packed red blood cells (p < 0.001) and plasma (p < 0.001), but not platelet (p = 0.615). The incidence of deep vein thrombosis was comparable in the two groups (p = 0.460). Compared with FFP only, PCC + FFP demonstrated better survival rate, favorable clinical recovery and no elevation of thromboembolism events after TIC.

Comparison of Endotracheal Intubations Performed With Direct Laryngoscopy and Video Laryngoscopy Scenarios With and Without Compression: A Manikin-Simulated Study.

Optimal management for trauma-induced coagulopathy (TIC) is a clinical conundrum. In conjunction with the transfusion of fresh-frozen plasma (FFP), additional administration of prothrombin complex concentrate (PCC) was proposed to bring about further coagulative benefit. However, investigations evaluating the efficacy as well as corresponding side effects were scarce and inconsistent. The aim of this study was to systematically review current literature and to perform a meta-analysis comparing FFP+PCC with FFP alone. Web search followed by manual interrogation was performed to identify relevant literatures fulfilling the following criteria, subjects as TIC patients taking no baseline anticoagulants, without underlying coagulative disorders, and reported clinical consequences. Those comparing FFP alone with PCC alone were excluded. Comprehensive Meta-analysis software was utilized, and statistical results were delineated with odd ratio (OR), mean difference (MD), and 95% confidence interval (CI). I2 was calculated to determine heterogeneity. The primary endpoint was set as all-cause mortality, while the secondary endpoint consisted of international normalized ratio (INR) correction, transfusion of blood product, and thrombosis rate. One hundred and sixty-four articles were included for preliminary evaluation, 3 of which were qualified for meta-analysis. A total of 840 subjects were pooled for assessment. Minimal heterogeneity was present in the comparisons (I2 < 25%). In the PCC + FFP cohort, reduced mortality rate was observed (OR: 0.631; 95% CI: 0.450-0.884, p = 0.007) after pooling. Meanwhile, INR correction time was shorter under PCC + FFP (MD: -608.300 mins, p < 0.001), whilst the rate showed no difference (p = 0.230). The PCC + FFP group is less likely to mandate transfusion of packed red blood cells (p < 0.001) and plasma (p < 0.001), but not platelet (p = 0.615). The incidence of deep vein thrombosis was comparable in the two groups (p = 0.460). Compared with FFP only, PCC + FFP demonstrated better survival rate, favorable clinical recovery and no elevation of thromboembolism events after TIC.

Appropriateness of Using Vitamin K for the Correction of INR Elevation Secondary to Hepatic Disease in Critically ill Patients: An Observational Study.

BackgroundUsing vitamin K for correction of coagulopathy in critically ill patients is controversial with limited evidence. This study aims to evaluate the efficacy and safety of vitamin K in the correction of international normalized ratio (INR) elevation secondary to liver disease in critically ill patients.MethodA retrospective study of critically ill patients with coagulopathy secondary to liver disease. The primary outcome was to evaluate the association between vitamin K administration and the incidence of new bleeding events in critically ill patients with INR elevation; other outcomes were considered secondary. Patients were categorized into two groups based on vitamin K administration to correct INR elevation. The propensity score was generated based on disease severity scores and the use of pharmacological DVT prophylaxis.ResultsA total of 98 patients were included in the study. Forty-seven patients (48%) received vitamin K during the study period. The odds of the new bleeding event was not statistically different between groups (OR 2.4, 95% CI 0.28-21.67, P = .42). Delta of INR reduction was observed with a median of 0.63 when the first dose is given (P-value: <.0001). However the INR reduction with other subsequent doses of vitamin K was not statistically significant.ConclusionThe administration of vitamin K for INR correction in critically ill patients with coagulopathy secondary to liver disease was not associated with a lower odds of new bleeding events. Further studies are needed to assess the value of vitamin K administration in critically ill patients with liver diseases related coagulopathy.

Correction of international normalised ratio in major bleeding related to vitamin K antagonists is associated with better survival: A UK study

BackgroundThe association between international-normalised-ratio (INR) correction and mortality in patients with major bleeding on vitamin-K-antagonists (VKA) is important for evaluating the efficacy of reversal agents for oral anticoagulants. ObjectivesWe evaluate if INR correction (defined as ≤1.3) following intervention in major bleeding on VKA is associated with better survival, and if there is a dose-response relationship between Vitamin K (VK) and INR correction. MethodsData on patients' characteristics, haematological management and 30-day outcomes reported by 32 UK hospitals (October 2013–August 2016) were analysed. Associations between INR correction and: (a) 30-day mortality; (b) VK dose were estimated using multivariable logistic regression, using multiple imputation to handle missing INR values. ResultsOf 1771 patients, 77%, 73% and 33% received prothrombin-complex-concentrate (PCC), VK (92% intravenous) and red cells and fresh frozen plasma transfusion respectively. Proportionally more intracranial haemorrhage (ICH) cases (87%) than non-ICH cases (69%) received PCC. VK administration did not vary by ICH group, with 10 mg (33%) and 5 mg (28%) doses being the most common. Higher doses of VK (10 mg) were more likely to correct INR than lower doses (5 mg). Post-intervention INR > 1.3 in treated patients was associated with 3.2 (95%CI: 2.1–4.9) times higher odds of death within 30 days, compared with INR ≤ 1.3, with no difference between ICH and non-ICH. ConclusionsINR correction after intervention to manage major bleeding on VKA is associated with better survival. Higher VK doses (10 mg) improve INR correction more than lower doses (5 mg) in major bleeding, but further studies are warranted to compare the relative benefits/risks of 5 mg versus 10 mg doses.

Safety and effectiveness of a four-factor prothrombin complex concentrate for vitamin K antagonist reversal following a fixed-dose strategy

ObjectivesEarly reversal of anticoagulation improves outcomes in major bleeding and emergency surgery. To reverse vitamin K antagonists (VKA), vitamin K in addition to prothrombin complex concentrate (PCC) is recommended. Dosing...

International Normalized Ratio (INR) is Comparable to MELD in Predicting Mortality after Cholecystectomy

Guidelines suggest targeting a preoperative international normalized ratio (INR) < 1.5. We examined and compared the predictive value of INR relative to the Model for End-Stage Liver Disease (MELD). We reviewed the American College of Surgeons NSQIP from 2005 to 2016 for adult patients undergoing open or laparoscopic cholecystectomy. Patients with a preoperative INR were stratified into groups: ≤1, >1 to ≤1.5, >1.5 to ≤2, and >2. Thirty day postoperative mortality was the primary outcome. Multivariable logistic regressions controlled for baseline differences. Of 58,177 cholecystectomy patients, 15.2 per cent had INR ≤ 1, 80.4 per cent had INR > 1 to ≤1.5, 3.7 per cent had INR > 1.5 to ≤2, and 0.7 per cent had INR > 2. Patients with INR > 2 were older and more likely to have diabetes and hypertension (P < 0.001). Multivariable regression demonstrated a stepwise increase in mortality for INR > 1 to ≤1.5 (odds ratio (OR) = 1.50 [1.10-2.05]), INR > 1.5 to ≤2 (OR = 2.96 [1.97-4.45]), and INR > 2 (OR = 3.21 [1.64-6.31]) relative to INR ≤ 1. C-statistic for INR (0.910) and MELD (0.906) models indicated a similar value in predicting mortality. INR groups also faced an incremental, increased risk of bleeding. Although unable to track preoperative correction of INR, this analysis identifies that INR remains an excellent predictor of postoperative mortality and bleeding after both open and laparoscopic cholecystectomies and is comparable to MELD.

3-Factor Versus 4-Factor PCC in Coagulopathy of Trauma: Four is Better Than Three.

Coagulopathy of trauma (COT) is common and highly lethal. Prothrombin complex concentrate (PCC) has been advocated for correction of COT. However, the difference in efficacy between three-factor PCC (3-PCC) versus four-factor PCC (4-PCC) remains unclear. The aim of our study was to compare efficacy of 3-PCC versus 4-PCC in COT. Five-year (2013-2017) review of coagulopathic trauma patients at our Level-I trauma center who received 3- or 4-PCC. Patients were divided into two groups (4-PCC and 3-PCC) and matched in 1:1 ratio using propensity-score-matching for demographics, injury parameters, admission vitals, and hematological parameters. Primary outcomes were time to correction of international normalized ratio (INR), blood products transfusion, thromboembolic complications, and mortality. Secondary outcomes were hospital-length of stay (LOS), intensive care unit (ICU)-LOS, cost of therapy, and total hospital cost. Six hundred fifty-seven patients met inclusion criteria of whom 250 patients (4-PCC:125; 3-PCC:125) were matched. The mean age was 50 ± 19.4 y, 64% were male, and median-injury severity score was 24[15-33]. 4-PCC was associated with accelerated correction of INR (365 vs. 428 min, P = 0.01), decrease in red blood cells (7 units vs. 10 units, P = 0.04) and FFP (6 units vs. 8 units, P = 0.03) transfused. There was no difference in platelet transfusion, thromboembolic complications, mortality, hospital, and ICU-LOS. 4-PCC was associated with higher cost of PCC therapy, and lower cost of transfusion. There was no difference regarding the total hospital cost between the two groups. Compared with 3-factor PCC, the use of 4-factor PCC is associated with a rapid reversal of INR and reduction in transfusion requirement without increasing the overall hospital cost or the risk of thromboembolic events. 4-PCC may be preferred as an adjunct for the resuscitation of coagulopathic trauma patients.

AGA Clinical Practice Update: Coagulation in Cirrhosis.

This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. The intent is to evaluate the current data on mechanism of altered coagulation in patients with cirrhosis, provide guidance on the use of currently available testing of the coagulation cascade, and help practitioners use anticoagulation and pro-coagulants appropriately in patients with cirrhosis. This review is framed around the best practice points, which were derived from the most impactful publications in the area of coagulation in cirrhosis and agreed to by all authors. BEST PRACTICE ADVICE 1: Global tests of clot formation, such as rotational thromboelastometry, thromboelastography, sonorheometry, and thrombin generation, may eventually have a role in the evaluation of clotting in patients with cirrhosis, but currently lack validated target levels. BEST PRACTICE ADVICE 2: In general, clinicians should not routinely correct thrombocytopenia and coagulopathy before low-risk therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation in patients with hepatic synthetic dysfunction-induced coagulation abnormalities. BEST PRACTICE ADVICE 3: Blood products should be used sparingly because they increase portal pressure and carry a risk of transfusion-associated circulatory overload, transfusion-related acute lung injury, infection transmission, alloimmunization, and/or transfusion reactions. BEST PRACTICE ADVICE 4: The following transfusion thresholds for management of active bleeding or high-risk procedures may optimize clot formation in advanced liver disease: hematocrit ≥25%, platelet count >50,000, and fibrinogen >120 mg/dL. Commonly utilized thresholds for international normalized ratio correction are not supported by evidence. BEST PRACTICE ADVICE 5: Thrombopoietin agonists are a good alternative to platelet transfusion, but require time (about 10 days) to elevate platelet levels. BEST PRACTICE ADVICE 6: The large volume of fresh frozen plasma required to reach an arbitrary international normalized ratio target, limitations of the usual target, minimal effect on thrombin generation, and adverse effects on portal pressure limit the utility of this agent significantly. BEST PRACTICE ADVICE 7: The 4-factor prothrombin complex concentrate contains both pro- and anticoagulant factors that offer an attractive low-volume therapeutic to rebalance a disturbed hemostatic system. However, dosage is, in part, based on international normalized ratio, which is problematic in cirrhosis, and published experience in liver disease is limited. BEST PRACTICE ADVICE 8: Anti-fibrinolytic therapy may be considered in patients with persistent bleeding from mucosal oozing or puncture wound bleeding consistent with impaired clot integrity. Both ε-aminocaproic acid and tranexamic acid inhibit clot dissolution. Neither is believed to generate a hypercoagulable state, although both may exacerbate pre-existing thrombi. BEST PRACTICE ADVICE 9: Desmopressin releases von Willebrand factor as its primary hemostatic mechanism. As this factor is usually elevated in cirrhosis, the agent lacks a sound evidence-based foundation, but may be useful in patients with concomitant renal failure. BEST PRACTICE ADVICE 10: Systemic heparin infusion is recommended for symptomatic deep vein thrombosis and portal and mesenteric vein thrombosis, but there are unresolved issues regarding monitoring with both the anti-Xa assay and the partial thromboplastin time due to cirrhosis-related antithrombin deficiency (heparin cofactor). BEST PRACTICE ADVICE 11: Treatment of incidental portal and mesenteric vein thrombosis depends on estimated impact on transplantation surgical complexity vs risks of bleeding and falls. Therapy with low-molecular-weight heparin, vitamin K antagonists, and direct-acting anticoagulants improve portal vein repermeation vs observation alone. BEST PRACTICE ADVICE 12: Direct-acting anticoagulants, such as the factor Xa and thrombin inhibitors, are relatively safe and effective in stable cirrhotic patients, but are in need of further study in patients with more advanced liver disease.

Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage.

Author(s): Bower, Matthew M; Sweidan, Alexander J; Shafie, Mohammad; Atallah, Steven; Groysman, Leonid I; Yu, Wengui

Efficacy and safety of prothrombin complex concentrate for vitamin K antagonist-associated intracranial hemorrhage: a systematic review and meta-analysis.

Prothrombin complex concentrate (PCC) is the treatment of choice in vitamin K antagonist-associated intracranial hemorrhage (VKA-ICH). However, the efficiency and safety associated with their use remain unclear. This study aimed to assess the current evidence of the clinical outcomes in patients with VKA-ICH treated with or without PCC. A meta-analysis was conducted. Two randomized controlled trials and 19 observational studies were included. PCC use demonstrated a significant increased likelihood of international normalized ratio (INR) normalization (OR = 3.76; 95% CI 1.74-8.12), shortened time to INR correction (MD = - 1.30; 95% CI - 2.08 to - 0.53) and reduction of hematoma expansion (HE) rate (OR = 0.37; 95% CI 0.23-0.60). Although PCC use revealed a statistical reduction at 30-day mortality (OR = 0.62; 95% CI 0.50-0.78), the result was inconsistent with mortality at discharge (OR = 1.03; 95% CI 0.68-1.57) and 90-day follow-up (OR = 0.50; 95% CI 0.24-1.07), both of which yielded no significant difference. When subgroup analyses were performed focus on PCC only treatment with FFP, no statistically significant difference was observed in 30-day mortality (OR = 0.43; 95% CI 0.11-1.71) as well. Besides, significant difference was not found in neurologic improvement at discharge (OR = 1.85; 95% CI 0.32-10.75), 30-day follow-up (OR = 3.00; 95% CI 0.93-9.70), or 90-day follow-up (OR = 1.55; 95% CI 0.84-2.86). No statistically significant difference was noted in the risk of thromboembolism following PCC administration (OR = 0.61; 95% CI 0.23-1.63). PCC use for VKA-ICH reversal was associated with a significant reduction in INR and HE rate, without an increased risk of thromboembolic events. However, this reduction was not associated with improvement in neurologic deficits or overall survival. Well-designed randomized trials with special considerations to the aspect are necessary.

Safety and Outcomes of Transradial Access in Patients with International Normalized Ratio 1.5 or above

PurposeTo examine the safety and outcomes for patients undergoing transradial noncoronary interventions with international normalized ratio (INR) ≥1.5. Materials and MethodsA retrospective review of 2,271 transradial access (TRA) cases performed from July 2012 to July 2016 was conducted. Criteria for inclusion were moderate bleeding risk cases with preprocedure INR ≥1.5. Within the study period, there were 176 moderate bleeding risk procedures (transarterial chemoembolization: 70/176 [39.8%]; Barbeau B: 121/176 [68.8%]; 5-F sheath: 157/176 [89.2%]) performed on 122 patients (age 61.6 ± 12.1 years, 68.9% male, body mass index 28.0 kg/m2) with INR ≥1.5. ResultsTechnical success was achieved in 98.9% of cases. Grade 1/2 hematomas developed in 10 cases (5.7%). Age ≥65 years (P = .042) and female sex (P = .046) were predictive of access site bleeding complications. Fresh frozen plasma (FFP) transfusion was administered in 11.4% of cases (n = 20). Baseline INR and creatinine were significantly different between transfused and nontransfused cases (P values .006 and .028, respectively). Minor access site bleeding occurred in 3/20 cases (15%) receiving prior FFP transfusion and 7/156 nontransfused cases (4.5%), with no significant difference between these 2 groups (P = .072). ConclusionsTRA in patients with elevated INR appears to be safe in our experience. Age ≥65 years and female sex were associated with increased incidence of access site bleeding. Although INR correction was not standardized in this cohort, preprocedure FFP transfusion did not decrease bleeding complications.

Feasibility of a Collaborative, Prospective Interdisciplinary Review and Pharmacy-Based Dispensing Process for Prothrombin Complex Concentrate.

Therapeutic options for rapid reversal of vitamin K antagonist therapy include 4-factor prothrombin complex concentrate (PCC4) and fresh frozen plasma (FFP). These agents have unique requirements for preparation, potential adverse effects, and cost-effectiveness considerations. To retrospectively assess whether our process for collaborative prospective review and pharmacy preparation facilitates timely and safe warfarin reversal with PCC4 as compared with FFP and to compare effectiveness and safety of the agents in practice. We performed a retrospective, single-center, before and after cohort study of patients requiring warfarin reversal for life-threatening bleeding or urgent invasive procedures over an 18-month period. The primary end point was time from ordering of reversal agent to administration. Secondary end points measured time to therapeutic effect and rates of adverse events. Of 98 patients studied, 72 received FFP, and 26 received PCC4. The median times from ordering to administration of FFP and PCC4 were 69 and 44 minutes, respectively ( P = 0.015). Median time from ordering to end of infusion was significantly shorter for PCC4 compared with FFP (54 vs 151 minutes, respectively; P < 0.0001). In all, 72% of PCC4 patients and 28% of FFP patients achieved the goal international normalized ratio (INR) of ≤1.4 at the first INR check ( P < 0.0001). Adverse reactions occurred in 4% of patients in each group. In routine clinical practice incorporating collaborative prospective review and dispensing from the institution's pharmacy, PCC4 was associated with faster administration, a higher rate of INR correction, and similar rates of adverse events compared with FFP.

Knowledge and information levels and adherence to oral anticoagulant therapy with warfarin in patients attending primary health care services.

Background Oral anticoagulation therapy with warfarin is widely used around the world and its safety and efficacy are well-established. Nevertheless, anticoagulants are among the drug classes most associated with fatal medication errors in primary health care. Objective To investigate patient knowledge, the level of information provided, and medication adherence in patients treated with warfarin at a primary health care service. Method A cross-sectional study of a prospective cohort of 60 patients on warfarin treatment in the town of Ijuí, Rio Grande do Sul, Brazil. A questionnaire was administered to test patients’ knowledge about their prescriptions and the level of information provided by the health team. The 8-item Morisky Medication Adherence Scale (MMAS-8) and International Normalized Ratio (INR) were used to verify adherence to treatment. Results The results were expressed in absolute and relative values and prevalence ratios were calculated, with respective 95% confidence intervals. It was found that 83.3% of the participants had been given insufficient information by the health team, 50% did not know how to use the medication correctly, 86.7% were not adherent to the treatment according to MMAS-8 and 63.3% were outside of the correct INR range. Conclusion In this study, we observed a need to improve the quality of information provided to users and to develop strategies to improve adherence to treatment, to ensure the safety of patients treated with warfarin in primary health care services.

Impact of INR monitoring, reversal agent use, heparin bridging, and anticoagulant interruption on rebleeding and thromboembolism in acute gastrointestinal bleeding.

BackgroundAnticoagulant management of acute gastrointestinal bleeding (GIB) during the pre-endoscopic period has not been fully addressed in American, European, or Asian guidelines. This study sought to evaluate the risks of rebleeding and thromboembolism in anticoagulated patients with acute GIB.MethodsBaseline, endoscopy, and outcome data were reviewed for 314 patients with acute GIB: 157 anticoagulant users and 157 age-, sex-, and important risk-matched non-users. Data were also compared between direct oral anticoagulants (DOACs) and warfarin users.ResultsBetween anticoagulant users and non-users, of whom 70% underwent early endoscopy, no endoscopy-related adverse events or significant differences were found in the rate of endoscopic therapy need, transfusion need, rebleeding, or thromboembolism. Rebleeding was associated with shock, comorbidities, low platelet count and albumin level, and low-dose aspirin use but not HAS-BLED score, any endoscopic results, heparin bridge, or international normalized ratio (INR) ≥ 2.5. Risks for thromboembolism were INR ≥ 2.5, difference in onset and pre-endoscopic INR, reversal agent use, and anticoagulant interruption but not CHA2DS2-VASc score, any endoscopic results, or heparin bridge. In patients without reversal agent use, heparin bridge, or anticoagulant interruption, there was only one rebleeding event and no thromboembolic events. Warfarin users had a significantly higher transfusion need than DOACs users.ConclusionEndoscopy appears to be safe for anticoagulant users with acute GIB compared with non-users. Patient background factors were associated with rebleeding, whereas anticoagulant management factors (e.g. INR correction, reversal agent use, and drug interruption) were associated with thromboembolism. Early intervention without reversal agent use, heparin bridge, or anticoagulant interruption may be warranted for acute GIB.

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.

Assessing the Efficacy of Prothrombin Complex Concentrate in Multiply Injured Patients With High-Energy Pelvic and Extremity Fractures.

Prothrombin complex concentrate (PCC) is being increasingly used for reversing induced coagulopathy of trauma. However, the use of PCC for reversing coagulopathy in multiply injured patients with pelvic and/or lower extremity fractures remains unclear. The aim of our study was to assess the efficacy of PCC for reversing coagulopathy in this group of patients. Two-year retrospective analysis. Our level I trauma center. All coagulopathic [International normalized ratio (INR) ≥1.5] trauma patients. Patients with femur, tibia, or pelvic fracture were included. Patients were divided into 2 groups: PCC (single dose) and fresh frozen plasma (FFP). Patients in the 2 groups were matched using propensity score matching. Time to correction of INR, time to intervention, development of thromboembolic complications, mortality, and cost of therapy. A total of 81 patients (PCC: 27, FFP: 54) were included. Patients who received PCC had faster correction of INR and shorter time to surgical intervention in comparison to patients who received FFP. PCC therapy was also associated with lower overall blood product requirement (P = 0.02) and lower transfusion costs (P = 0.0001). In a matched cohort of multiply injured patients with pelvic and/or lower extremity fractures, administration of a single dose of PCC significantly reduced the time to correction of INR and time to intervention compared with patients who received FFP therapy. This may allow orthopaedic surgeons to more safely proceed with early, definitive fixation strategies. Therapeutic level III. See Instructions for Authors for a complete description of levels of evidence.