Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy

Aims

The purpose of this study was to evaluate the effectiveness of a new, fixed, yet individualized dosing regimen of activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for warfarin reversal in the setting of a life-threatening bleeding in a secondary care center.

Methods

In this report we present a retrospective chart review of 72 patients who received FEIBA and 69 patients who received fresh-frozen plasma (FFP) to reverse the effects of warfarin in a setting of a life-threatening bleeding. In the FEIBA cohort, patients received 500 units of FEIBA when the initial INR was <5 or 1,000 units of FEIBA when initial INR was ≥5.

Results

FEIBA administration resulted in lower subsequent INR when compared with FFP and shorter time elapsed from drug administration to an INR ≤1.4 when compared with FFP. No significant differences in survival or in the length of hospital stay were observed. A higher FEIBA dose induced a bigger decrease in INR than the lower dose. We observed five adverse events (7%) that could potentially be related to FEIBA administration.

Conclusions

The presented dosing regimen results in safe reversal of warfarin-induced coagulopathy, which appears to be faster and more profound than following FFP. Moreover, the use of activated PCC (FEIBA) does not appear to carry an increased risk of thrombotic events when compared to the rate reported for several non-activated PCC preparations.     

Evaluation of Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal in Patients with Intracranial Hemorrhage

Background

Different strategies exist for dosing four-factor prothrombin complex concentrate (PCC4) for international normalized ratio (INR) reversal in the setting of life-threatening bleeding. Fixed doses ranging from 1000 IU to 1750 IU have demonstrated efficacy similar to weight-based dosing, however, few studies look exclusively at intracranial hemorrhage (ICH).

A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal

Introduction

Prothrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage.

Methods

We performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the international normalised ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs).

Results

A total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and ≤1.5 in all patients of both groups - 10 minutes after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 minutes (P = 0.001), 1 hour (P = 0.001) and 3 hours (P = 0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (P = 0.038), FII (P = 0.001), FX (P <0.001), protein C (P = 0.002) and protein S (0.043), 10 minutes after infusion. However, no differences were found in haematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups.

Conclusions

Rapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality.

Trial registration

Eudra CT number 2007-000602-73.     

Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED

Objectives

High International Normalized Ratio (INR) level resulting from warfarin use increases the risk of gastrointestinal hemorrhages. We aimed to compare the efficacy of prothrombin complex concentrates (PCC) and fresh frozen plasma (FFP) at lowering the INR level, decreasing active hemorrhages visible by endoscopy, and shortening the length of stay at the emergency department (ED).

Method

This study is a prospective cohort study of consecutive patents with gastrointestinal hemorrhages that received either PCC or FFP. With strict exclusion criteria, only patients over 18 years of age with a high INR level (> 2.1) due to warfarin usage were included.

Results

A total of 40 patients (18 female) were included in the study, 20 each in the PCC and FFP groups. For the PCC group, the mean INR levels at the second and sixth hours were lower than those for the FFP group (second hour INR: 1.53 vs 4.50, P < .01, sixth hour INR: 1.52 vs 2.41, P < .01). Seven patients experienced active bleeding (Forrest 1) in the FFP group, whereas no patient experienced active bleeding in the PCC group based on the Forrest classification (35% vs 0%, P < .01), and only 3 patients in the FFP group underwent invasive/surgical treatment (15% vs 0%, P < .01). The ED length of stay was lower for the PCC group (1.62 days vs 3.46 days, P < .01).

Conclusion

For patients experiencing a gastrointestinal hemorrhage, INR levels were reversed more quickly, there was less active bleeding on endoscopy, and the ED length of stay was lower in the PCC group than in the FFP group.     

Evaluation of an initiation protocol of 4 mg of warfarin for atrial fibrillation in the outpatient setting

Objective

To describe the efficacy and safety of an initiation algorithm for 4 mg of warfarin in ambulatory patients with atrial fibrillation.

Design

Prospectively planned retrospective chart review.

Setting

Centre for Family Medicine Family Health Team in Kitchener, Ont.

Participants

Ambulatory patients requiring anticoagulation for atrial fibrillation.

Interventions

Patients were prescribed 4 mg of warfarin to be taken once daily for 3 days. An international normalized ratio (INR) measured on the morning of the fourth day was used to predict the maintenance dose of warfarin. Subsequent INR measurements were obtained biweekly until patients reached their actual maintenance dose.

Main outcome measures

Number of INR values greater than or equal to 4.0 before the warfarin maintenance dose was achieved. Secondary outcome measures included thromboembolic and bleeding events, number of days required to reach therapeutic INR, and correlation between predicted and actual warfarin maintenance dose.

Results

Twenty-five patients were included in the study. The average age was 76.0 years (range 56.0 to 89.0), and 17 patients were women. The average CHADS₂ (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, and stroke or transient ischemic attack) score was 2.0. Only 1 patient had an INR greater than 4.0 during the study period. The mean time to achieve a therapeutic INR was 11.0 days. The day 4 INR was moderately predictive of the maintenance dose (r² = 0.47). There were no adverse events that required medical attention during the study period.

Conclusion

In this pilot study, an initiation algorithm for 4 mg of warfarin was safe and achieved a therapeutic INR within a reasonable time frame in outpatients with atrial fibrillation.     

Reversal of Vitamin K Antagonist (VKA) effect in patients with severe bleeding: a French multicenter observational study (Optiplex) assessing the use of Prothrombin Complex Concentrate (PCC) in current clinical practice

Introduction

Prothrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008.

Methods

All consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex^®) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion.

Results

Of 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 ± 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 ± 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 ± 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR.

Conclusions

Severe bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes.     

Bilateral Phlegmasia Cerulea Dolens After Warfarin Reversal for Acute Rectal Bleeding: A Case Report

Background

Deep vein thrombosis (DVT) is a common disease that is diagnosed in approximately 1 in 1000 adults annually. Extensive DVT can lead to life- or limb-threatening diagnoses such as phlegmasia cerulea dolens (PCD), phlegmasia alba dolens, and venous gangrene. PCD, also known as massive iliofemoral venous thrombosis, is rare, and a severe complication of DVT.

High doses of warfarin are more beneficial than its low doses in patients with deep vein thrombosis

Background

The efficacy and safety of enoxaparin in outpatient treatment of deep vein thrombosis have been well studied. The present study aimed to compare the efficacy of a 10-mg loading dose of warfarin with 5 mg of the drug and enoxaparin in achieving the international normalized ratio (INR) range.

Methods

This randomized clinical trial was performed in the emergency department (ED) of our study. International normalized ratio was checked daily for 7 days and on the 14th day. Based on the patient's INR on the third day, the doses were adjusted. Patients received enoxaparin (1.5 mg/kg per day) simultaneously until the therapeutic range of INR was achieved for 2 consecutive days.

Result

The side effects were compatible in both groups. There was a significant difference in the INR rates of the 2 groups recorded on the third, fourth, and seventh days.

Conclusion

The 10-mg loading dose of warfarin induces the therapeutic range of INR earlier than the 5-mg dose without causing any significant difference in the side effects. More cases in the 10-mg group had INR levels higher than 3; the very dose, therefore, is recommended as the loading dose in cases of outpatients with deep vein thrombosis referring to the ED. Tight control of INR, after the third day of treatment, is also recommended in these cases.     

Factor Eight Inhibitor Bypassing Agent (FEIBA) for Reversal of Target-Specific Oral Anticoagulants in Life-Threatening Intracranial Bleeding

Introduction

As increasing number of patients present to emergency departments with life threatening hemorrhages, particularly intracranial hemorrhage on anticoagulation physicians must be cognizant of the limitations of the available reversal options. Based upon the available literature, our institution formulated a reversal algorithm for patients with life-threatening bleeding on factor Xa inhibitors by administering factor eight inhibitor bypassing agent (FEIBA) 20 units/kg.

Protocolized use of Factor Eight Inhibitor Bypassing Activity (FEIBA) for the reversal of warfarin induced coagulopathy

IntroductionCoagulopathy due to warfarin in patients with major bleeding was traditionally reversed with fresh frozen plasma and intravenous (IV) vitamin K, but prothrombin complex concentrates (PCC) are increasingly used in the treatment of these patients. Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated four-factor PCC most commonly used in patients with hemophilia. We aimed to evaluate the efficacy and safety of FEIBA and IV vitamin K for the reversal of warfarin-associated coagulopathy in patients with major bleeding, by measuring the percentage of patients who achieved target INR ≤ 1.5 and the incidence of thrombotic adverse events (TAE).MethodsIn this prospective observational study, we enrolled patients presenting to the Emergency Department (ED) with warfarin associated coagulopathy (INR > 1.5) and major bleeding. Patients received FEIBA using an INR based dosing strategy and IV vitamin K.ResultsIn 43 patients, median initial INR was 4.0 (2.7, 7.3 interquartile range (IQR)). Median time to result the second INR was 45 min (38, 55 IQR) and the median INR was 1.4 (1.3, 1.6 IQR). Out of the 43 patients, 93% achieved the target INR of ≤1.5. In-hospital mortality was 40% (17 patients). There were 11 TAEs in 6 patients (14%); 4 events in 2 patients (5%) were attributed to FEIBA.ConclusionA protocolized use of FEIBA and IV vitamin K resulted in the efficacious reversal of warfarin-induced coagulopathy in patients with major bleeding. TAEs occurred in 14% of patients and were attributed to FEIBA in 5% of patients.     

Air Ambulance Delivery and Administration of Four‐factor Prothrombin Complex Concentrate Is Feasible and Decreases Time to Anticoagulation Reversal

Objectives

The objective was to evaluate the feasibility, safety, and preliminary efficacy of four‐factor prothrombin complex concentrate (4‐factor PCC) administration by an air ambulance service prior to or during transfer of patients with warfarin‐associated major hemorrhage to a tertiary care center for definitive management (interventional arm) compared to patients receiving 4‐factor PCC following transfer by air ambulance or ground without 4‐factor PCC treatment (conventional arm).

Methods

This was a retrospective chart review of patients presenting to a large academic medical center. All patients presenting to the emergency department (ED) treated with 4‐factor PCC from April 1, 2014, through June 30, 2016, were identified. For this study, only transfer patients with an International Normalized Ratio (INR) > 1.5 actively treated with warfarin were included. The primary outcome was the proportion of patients with an INR ≤ 1.5 upon tertiary care hospital arrival, and the secondary efficacy outcome was difference in time to achievement of INR ≤ 1.5. Additional safety and efficacy objectives included difference in thromboembolic complications, length of stay, intensive care unit length of stay, and inpatient mortality between groups.

Results

Of the 72 included patients, a higher proportion of patients in the interventional group had an INR ≤ 1.5 on ED arrival (proportion difference = 0.82, 95% confidence interval = 0.64–0.92, p < 0.0001) and significantly reduced time to observed INR ≤ 1.5 (181 minutes vs. 541 minutes, p = 0.001). No differences were observed in thromboembolic complications or patient‐centered outcomes with the exception of mortality, which was significantly higher in patients in the interventional group. This group was also observed to have lower Glasgow Coma Scale score and higher intubation rates prior to transfer and treatment.

Conclusions

Dispatch of an air ambulance carrying 4‐factor PCC with administration prior to transfer is feasible and leads to more rapid improvement in INR among patients with warfarin‐associated major hemorrhage.

     

Warfarin Poisoning with Delayed Rebound Toxicity

Background

Intentional poisoning with warfarin is not the same as over-anticoagulation, for which guidelines exist. The coagulopathy resulting from a warfarin overdose is reversed with vitamin K₁, the dose and timing of which is often guided by experience with the management of over-anticoagulation with warfarin therapy, rather than acute overdose.

Multi-centered evaluation of a novel fixed-dose four-factor prothrombin complex concentrate protocol for warfarin reversal

IntroductionPrevious studies have shown fixed-dose 4PCC to be as effective as standard-dose 4PCC for warfarin reversal. However, certain patient populations such as those with high total body weight (TBW) or elevated baseline INR may be at increased risk for treatment failure. The purpose of this study was to validate the efficacy of a novel fixed-dose 4PCC protocol for warfarin reversal.MethodsThis was a multi-centered observational comparison of patients who received 4PCC for warfarin reversal. Fixed-dose patients received 1500 units of 4PCC with the dose increased to 2000 units in patients with a baseline INR ≥ 7.5, a TBW ≥ 100 kg, or for intracranial hemorrhage (ICH). Standard-dosing followed manufacturer recommendations. The primary outcome was achievement of a post-4PCC INR of ≤1.4. Secondary outcomes included target INR achievement among patients with a baseline INR ≥ 7.5, a TBW ≥ 100 kg, or neurologic bleeding indications; hospital length of stay; cost of therapy; and thromboembolic complications.ResultsA total of 116 patients were included in the standard-dose group and 75 in the fixed-dose group. There was no difference in the primary outcome (65% vs 57%, p = 0.32). There was no difference in secondary outcomes aside from cost of therapy in which fixed-dose 4PCC was less expensive than standard-dose 4PCC.ConclusionA fixed-dose 4PCC regimen for warfarin reversal of 1500 units, with an increased dose of 2000 units for select patients, is as effective as standard-dose 4PCC for INR reversal.     

The Clinical Use of Prothrombin Complex Concentrate

Background

Prothrombin complex concentrate (PCC) is an inactivated concentrate of factors II, IX, and X, with variable amounts of factor VII. Guidelines recommend the use of PCC in the setting of life-threatening bleeds, but little is known on the most effective dosing strategies and how the presenting international normalized ratio affects response to therapy.

Objectives

This review aims to highlight available data on monitoring techniques, address shortcomings of currently available data, the reversal of life-threatening and critical bleeds with PCC, and how this product compares to other therapeutic options used in critically ill patients.

Discussion

PCC has been identified as a potential therapy for critically bleeding patients, but patient-specific factors, product availability, and current data should weigh the decision to use it. Most data exist regarding patients experiencing vitamin K antagonist-induced bleeding, more specifically, those with intracranial hemorrhage. PCC has also been studied in trauma-induced hemorrhage; however, it remains controversial, as its potential benefits have the abilities to become flaws in this setting.

Conclusion

Health care professionals must remain aware of the differences in products and interpret how three- versus four-factor products may affect patients, and interpret literature accordingly. The clinician must be cognizant of how to progress when treating a bleeding patient, propose a supported dosing scheme, and address the need for appropriate factor VII supplementation. At this point, PCC cannot be recommended for first-line therapy in patients with traumatic hemorrhage, and should be reserved for refractory bleeding until more data are available.     

Fixed-dose prothrombin complex concentrate for emergent warfarin reversal among patients with intracranial hemorrhage

IntroductionFour-factor prothrombin complex concentrate (4PCC) is the preferred reversal agent for warfarin reversal, although the ideal dose is unknown. Fixed-dose 4PCC offers simplified dosing compared to standard-dosing algorithms with potentially lower risks of thromboembolic complications given lower doses are typically utilized.MethodsRetrospective, observational, multicentered, pre- post- study of patients who received 4PCC for warfarin reversal among four hospitals within the same regional health system. Standard-dose patients received variable doses ranging from 25 to 50 units/kg based on total body weight and initial INR and fixed-dose patients received 2000 units. The primary outcome was achievement of a target INR ≤ 1.4 on the first post-4PCC INR result.ResultsAfter exclusions, 48 and 42 patients were analyzed in the standard-dose and fixed-dose groups, respectively. There was no difference in the ability to achieve a target INR of ≤1.4 (82.6% vs 81.5%, p = 0.14). Both groups received the same median dose of 2000 units, although fixed-dose patients actually received a higher weight-based dose than standard-dose patients (27 units/kg vs 24.5 units/kg).ConclusionA fixed-dose 4PCC regimen of 2000 units among patients with ICH was as effective as standard-dose 4PCC for INR reversal among patients with ICH. However, fixed-doses of 2000 units at times exceeded standard 4PCC doses which may be contradictory to the goals of fixed-dose 4PCC for warfarin reversal.     

Patient self-management of warfarin therapy: pragmatic feasibility study in Canadian primary care

Objective

To investigate the effectiveness of patient self-management (PSM) of anticoagulation using warfarin in a typical primary care site in Canada and to determine the feasibility of conducting a future large-scale trial in this setting.

Design

An 8-month pragmatic open-label randomized crossover trial.

Setting

A typical Canadian primary care practice in British Columbia.

Intervention

Patients were randomized to PSM or physician management for 4 months, after which allocation was reversed. The PSM group members were instructed to monitor their serum international normalized ratio (INR) at community laboratories and to adjust their warfarin doses independently using provided nomograms. Education on warfarin dose adjustment was limited to a single 15-minute office visit.

Main outcome measures

The primary outcome was the proportion of INR values in the therapeutic range among participants. Feasibility outcomes included proportion of eligible patients consenting, patients’ preference of management strategy, patients’ satisfaction, and visits or phone communication with physicians regarding dose adjustment. Safety outcomes included bleeding or thromboembolic events.

Results

Eleven patients completed the trial, contributing 99 patient-months of monitoring and providing 122 INR measures. The mean proportion of INR values in therapeutic range among subjects in the PSM and physician-management groups was 82% and 80%, respectively (P = .82). The improvement in patient satisfaction with PSM was not significant. Ten of the 11 patients preferred PSM to physician management and elected to continue with this strategy after study completion (P = .001). No calls or visits were made to the physician regarding dose adjustment during the PSM period. There were no episodes of major bleeding or thromboembolic events.

Conclusion

Patient self-management was not demonstrated to be superior to standard care, but was easily implemented and was the method preferred by patients. Our feasibility outcomes justify a larger trial and suggest that subject recruitment and protocol adherence would not pose barriers for such a study.

Trial registration number

{"type":"clinical-trial","attrs":{"text":"NCT00925028","term_id":"NCT00925028"}}NCT00925028 (ClinicalTrials.gov).     

Monitoring of international normalized ratios: Comparison of community nurses with family physicians

Objective

To determine whether community-based, nurse-led monitoring of the international normalized ratio (INR) in patients requiring long-term warfarin therapy was comparable to traditional physician monitoring.

Design

A retrospective cohort analysis of patients taking long-term warfarin therapy.

Setting

The study used data gathered from 3 family medicine clinics in a primary care network in Edmonton, Alta.

Participants

Medical records of patients currently taking warfarin were examined.

Intervention

Implementation of nurse-led monitoring in a primary care network in place of standard family physician INR monitoring.

Main outcome measures

The degree of INR control before and after the implementation of nurse-run INR monitoring was assessed. The average proportion of time spent outside of therapeutic INR ranges, as well as the average number of days between successive INR readings, was calculated and compared. The degree of control placed patients into either a good-control group (out of range ≤ 25% of the time) or a moderate-control group (out of range > 25% of the time) and these groups were compared.

Results

Before nurse monitoring, INR values were out of range 20.4% of the time; after nurse monitoring they were out of range 19.2% of the time (P = .115); the time between sequential INR readings also did not differ before and after implementation of nurse monitoring (23.9 vs 21.6 days, P = .789).

Conclusion

Nurse-led monitoring of INR is as effective as traditional physician monitoring. Advantages of nurse-led monitoring might include freeing family physicians to see more patients or to spend less time at work. It might also represent potential cost savings.     

Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital

Introduction

Major blood loss can often be life-threatening and is most commonly encountered in the settings of surgery and trauma. Patients receiving anticoagulant therapy are also at increased risk of bleeding. We investigated the use of a prothrombin complex concentrate (PCC; Beriplex P/N, CSL Behring, Marburg, Germany) to treat severe bleeding in a variety of settings: cardiac surgery, warfarin therapy and other surgery.

Methods

Thirty consecutive patients who had received PCC were identified from blood transfusion records. For cardiac surgery and warfarin reversal, PCC was administered in accordance with hospital protocols. PCC was administered to cardiac and other surgical patients responding poorly to recognized blood products, whereas it was administered first-line to patients with life-threatening bleeds and requiring warfarin reversal, in accordance with British Committee for Standards in Haematology guidelines. We conducted a retrospective analysis of patient records in order to ascertain PCC dose, use of other blood products and response to PCC (clotting screen results before and after PCC administration, haemostasis achievement, and survival).

Results

Six patients (20%) were excluded because of inadequate documentation (n = 5) or acquired haemophilia (n = 1). Therefore, 24 patients were included in the analysis: coronary artery bypass graft (n = 5), mitral/aortic valve replacement (n = 2), other surgery (n = 9) and warfarin reversal (n = 8). Most patients (83.3%) received no more than 1500 IU of Beriplex P/N 500. Considerable reduction in administration of other blood products was seen during the 24 hours after PCC administration. Partial or complete haemostasis was achieved in 14 out of 18 cases (77.8%). In total, 12 out of 24 patients (50%) died during the study; two-thirds of the deaths were considered unrelated to bleeding. No thrombotic complications or adverse drug reactions were observed.

Conclusion

This study emphasizes the value of PCC in reversing the effects of oral anticoagulant therapy in bleeding patients. It also demonstrates the potential value of PCC in controlling bleeding in patients undergoing cardiac and other surgical procedures. The use of PCC in bleeding patients without hereditary or anticoagulation-related coagulopathy is novel, and further investigation is warranted. In the future, it may be possible to use PCC as a substitute for fresh frozen plasma in this setting; adequate documentation is crucial for all blood products.     

Management of Dabigatran-associated Intracerebral and Intraventricular Hemorrhage: A Case Report

Background

Dabigatran is an oral, reversibly bound, direct thrombin inhibitor currently approved in the United States for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In the phase III trial leading to approval of the agent, the incidence of life-threatening bleeding was 1.80%/year in the dabigatran 150 mg twice daily arm. Because there is no direct antidote or reversal agent for this drug, the need to manage life-threatening hemorrhages with procoagulant products will arise.

Objective

To describe a case of dabigatran-associated intracerebral and intraventricular hemorrhage and subsequent management with activated prothrombin complex concentrate.

Case Report

An 85-year-old man currently taking dabigatran 150 mg twice daily presented to the Emergency Department for incoordination, expressive aphasia, and weakness. A computed tomography image of his head demonstrated an intracranial hemorrhage. The last dose of dabigatran was approximately 14 h prior to arrival, and conventional coagulation assays (thrombin time and activated partial thromboplastin time) confirmed the presence of dabigatran in the patient's serum. The patient received 27.5 units/kg of activated prothrombin complex concentrate (FEIBA®; Baxter Healthcare Corporation, Deerfield, IL) after an initial intravenous fluid bolus. His activated partial thromboplastin time was not completely normalized by the use of FEIBA; however, the patient's neurological examination slightly improved and remained stable throughout his hospital course despite some intraventricular expansion of the hematoma. After discharge to physical rehabilitation, the patient developed an ischemic cerebrovascular accident and was discharged home on hospice.

Conclusion

Due to lack of an available antidote, activated prothrombin complex concentrate was utilized as a nonspecific procoagulant to stabilize an intracerebral hemorrhage in a patient on dabigatran.     

Extended International Normalized Ratio testing intervals for warfarin‐treated patients

Essentials

• Warfarin typically requires International Normalized Ratio (INR) testing at least every 4 weeks.
• We implemented extended INR testing for stable warfarin patients in six anticoagulation clinics.
• Use of extended INR testing increased from 41.8% to 69.3% over the 3 year study.
• Use of extended INR testing appeared safe and effective.

Summary

Background

A previous single‐center randomized trial suggested that patients with stable International Normalized Ratio (INR) values could safely receive INR testing as infrequently as every 12 weeks.

Objective

To test the success of implementation of an extended INR testing interval for stable warfarin patients in a practice‐based, multicenter collaborative of anticoagulation clinics.

Methods

At six anticoagulation clinics, patients were identified as being eligible for extended INR testing on the basis of prior INR value stability and minimal warfarin dose changes between 2014 and 2016. We assessed the frequency with which anticoagulation clinic providers recommended an extended INR testing interval (> 5 weeks) to eligible patients. We also explored safety outcomes for eligible patients, including next INR values, bleeding events, and emergency department visits.

Results

At least one eligible period for extended INR testing was identified in 890 of 3362 (26.5%) warfarin‐treated patients. Overall, the use of extended INR testing in eligible patients increased from 41.8% in the first quarter of 2014 to 69.3% in the fourth quarter of 2016. The number of subsequent out‐of‐range next INR values were similar between eligible patients who did and did not have an extended INR testing interval (27.3% versus 28.4%, respectively). The numbers of major bleeding events were not different between the two groups, but rates of clinically relevant non‐major bleeding (0.02 per 100 patient‐years versus 0.09 per 100 patient‐years) and emergency department visits (0.07 per 100 patient‐years versus 0.19 per 100 patient‐years) were lower for eligible patients with extended INR testing intervals than for those with non‐extended INR testing intervals.

Conclusions

Extended INR testing for stable warfarin patients can be successfully and safely implemented in diverse, practice‐based anticoagulation clinic settings.