Real-world utilization of andexanet alfa

ObjectiveIn 2018, the FDA approved andexanet alfa for the reversal of life-threatening hemorrhages in patients anticoagulated with apixaban or rivaroxaban. Yet, cost-effective factor Xa inhibitor reversal remains controversial. The objective of this study was to describe real world utilization of andexanet alfa.MethodsThis was a retrospective case series of patients receiving andexanet alfa between July 28, 2018 and April 29, 2019 at a large academic health system. Baseline demographics, anticoagulant type and reversal, as well as brain imaging were collected. Primary endpoints were stability of hematoma for intracranial hemorrhage (ICH), and hemostatic effectiveness for patients undergoing surgical procedures. Secondary endpoints were thromboembolism and 30 day mortality.ResultsOf the 25 patients evaluated, 13 received andexanet alfa for ICH. Eleven of the 13 had follow-up imaging available and stability was observed in 90.9%. Three patients received andexanet alfa for reversal prior to surgical procedures, and 100% hemostatic effectiveness was achieved. Nine patients received andexanet alfa for reversal of extracranial bleeding, including gastrointestinal bleed (n=4). There were no thrombotic events in our cohort, and 30 day mortality was 24%. Sixty-four percent of patients would have met exclusion criteria for the ANNEXA-4 trial.ConclusionThis is the largest series to date describing real-world utilization of andexanet alfa. Our series showed hemostatic efficacy in 90.9% of patients with ICH, and 100% in patients undergoing surgical procedures. There were no thrombotic complications. Yet, larger and comparative studies are needed to clarify the optimal agent and patient selection for reversal of factor Xa inhibitors.     

Four-factor prothrombin complex concentrate for life-threatening bleeds or emergent surgery: A retrospective evaluation

PurposePrevious trials investigating usage of four-factor prothrombin complex concentrate (4F-PCC) excluded patients with various thrombotic risk factors. The objective of this study was to evaluate the safety and effectiveness of 4F-PCC in a real-world setting based on an institutional protocol that does not have strict exclusion criteria.MethodsThis was a retrospective study of adult patients who received 4F-PCC. The primary outcome was a confirmed thromboembolism within 14 days after 4F-PCC administration. Secondary outcomes included international normalized ratio (INR) correction to <1.5 at first draw and incidence of INR rebound for patients undergoing reversal of warfarin and hemostatic effectiveness for patients experiencing a bleed.ResultsNinety-three patients received 4F-PCC. Sixty-three (67.7%) were reversed for bleeding and 30 (32.3%) for surgery. Eleven patients (11.8%) developed a thromboembolism within 14 days. The median (interquartile range) time to event was 5 (2-7) days. Significant risk factors were heparin-induced thrombocytopenia (P= .01) and major surgery within 14 days (P= .02), as well as the presence of >6 thrombotic risk factors (P= .01). For patients post-warfarin reversal, 45/63 (71.4%) achieved INR correction at first draw, 55/63 (87.3%) achieved INR correction within 24 hours, and 14/55 (25.5%) experienced INR rebound. Of these 14 patients, 8 (57.1%) did not receive concomitant vitamin K.Conclusions4F-PCC was associated with a notable thromboembolic risk. All patient-specific risk factors should be considered prior to administration. 4F-PCC remains a useful agent for warfarin reversal. Lack of concomitant vitamin K may contribute to INR rebound.     

Is there a difference in efficacy,safety, and cost-effectiveness between 3-factor and 4-factor prothrombin complex concentrates among trauma patients on oral anticoagulants?

PurposeThe aim of this study was to compare the efficacy, safety, and cost-effectiveness of 3-factor prothrombin complex concentrate (3F-PCC) vs 4-factor prothrombin complex concentrate PCC (4F-PCC) in trauma patients requiring reversal of oral anticoagulants.Materials and methodsAll consecutive trauma patients with coagulopathy (international normalized ratio [INR] ≥ 1.5) secondary to oral anticoagulants who received either 3F-PCC or 4F-PCC from 2010 to 2014 at 2 trauma centers were reviewed. Efficacy was determined by assessing the first INR post–PCC administration, and successful reversal was defined as INR less than 1.5. Safety was assessed by reviewing thromboembolic events, and cost-effectiveness was calculated using total treatment costs (drug acquisition plus transfusion costs) per successful reversal.ResultsForty-six patients received 3F-PCC, and 18 received 4F-PCC. Baseline INR was similar for 3F-PCC and 4F-PCC patients (3.1 ± 2.3 vs 3.4 ± 3.7, P = .520). The initial PCC dose was 29 ± 9 U/kg for 3F-PCC and 26 ± 6 U/kg for 4F-PCC (P = .102). The follow-up INR was 1.6 ± 0.6 for 3F-PCC and 1.3 ± 0.2 for 4F-PCC (P = .001). Successful reversal rates in patients were 83% for 4F-PCC and 50% for 3F-PCC (P = .022). Thromboembolic events were observed in 15% of patients with 3F-PCC vs 0% with 4F-PCC (P = .177). Cost-effectiveness favored 4F-PCC ($5382 vs $3797).ConclusionsThree-factor PCC and 4F-PCC were both safe in correcting INR, but 4F-PCC was more effective, leading to better cost-effectiveness. Replacing 3F-PCC with 4F-PCC for urgent coagulopathy reversal may benefit patients and institutions.     

Government Medicine Could Never Build a Drive-Up,No-Waiting-Room Clinic!

Abstract

The new oral anticoagulants have many advantages over vitamin K antagonists, but they are still associated with a troublesome incidence of major bleeding. Additionally, the absence of a reversal agent for the new oral anticoagulants is a barrier to their more widespread use. Currently, there are 3 potential reversal agents in development: idarucizumab is a humanized murine monoclonal antibody fragment directed specifically at dabigatran; andexanet alfa is a recombinant modified decoy factor Xa that binds to factor Xa inhibitors; and PER977 is a small molecule that binds to factor Xa and IIa inhibitors and to heparin-based anticoagulants through charge interaction. These agents have undergone phase I clinical testing, appear to be well tolerated in healthy volunteers, and are effective in neutralizing their respective targets. All 3 are currently undergoing or entering into a phase II or III clinical study. This article reviews the available data for idarucizumab, andexanet alfa, and PER977.     

Andexanet alfa for the reversal of factor Xa inhibitors

Introduction: Andexanet alfa is a recombinant modified factor Xa protein that has been developed to reverse factor Xa inhibitors. Since May 2018, the FDA has approved its utilization in patients treated with apixaban and rivaroxaban in case of life-threatening or uncontrolled bleeding. On 28 of February 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorization for andexanet alfa in Europe.

Area covered: The authors provide an overview of andexanet alfa development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial ANNEXA as well as current limitations related to andexanet alfa are also discussed.

Expert opinion: Although phase I and II studies have proven that andexanet alfa can be effective in reversing the effect of factor Xa inhibitors, its efficacy in major bleeding patients has only been shown for apixaban and rivaroxaban, without any comparator group. Well-designed studies comparing the efficacy and safety of andexanet alfa to other reversal strategies are required to confirm preliminary data. The benefit of andexanet alfa in specific settings needs to be investigated and its use in clinical practice needs to be facilitated by the implementation of international guidelines.     

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.     

Four-factor prothrombin complex concentrate dose response relationship with INR for warfarin reversal

IntroductionFor reversal of warfarin-induced coagulopathy, FDA labeling of four-factor prothrombin complex concentrate (4F-PCC) endorses a dosing strategy based on body weight and baseline INR. Recent literature suggests lower, fixed doses of 4F-PCC may be equally efficacious. The present evaluation aims to characterize the relationship between 4F-PCC dose and degree of reduction in INR.MethodsThis is a retrospective, single-center review of 4F-PCC administrations for warfarin reversal between May 2014 and August 2017. The primary endpoint evaluates the relationship between doses of 4F-PCC and INR measurement after reversal, represented as a linear regression. Exploratory endpoints characterize the relationships of both body weight and baseline INR, the components determining initial 4F-PCC dose, with INR after reversal. Additionally, for records presenting with an INR of 2–3.9, mean INR after reversal was characterized as a function of two 4F-PCC dose cohorts (< 30 and ≥30 IU fIX/kg).ResultsA significant linear relationship between 4F-PCC dose and INR after reversal (INR after 4F-PCC = 1.3651–0.00004(4F-PCC Dose), p = 0.0071, R² = 0.0630) was observed. Body weight and baseline INR were not correlated with INR after reversal. The subgroup analysis of records with presenting INR of 2–3.9 demonstrated no difference in mean INR after reversal with 4F-PCC for those receiving <30 IU fIX/kg and those receiving ≥30 IU fIX/kg.ConclusionThis evaluation found no clinically relevant relationship with 4F-PCC doses and degree of INR reversal. Further prospective study is required to determine optimal dosing schemes of 4F-PCC for warfarin reversal.     

Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage

ObjectiveThe objective of this study was to determine the effectiveness and safety of four-factor prothrombin complex concentrate (4F-PCC) for the reversal of factor Xa inhibitors in patients with traumatic intracranial hemorrhage (ICH).MethodsThis was a retrospective cohort study of patients taking factor Xa inhibitors with traumatic ICH between March 1, 2015 and August 31, 2017 at two trauma centers. The primary outcome was in-hospital mortality in patients who received 4F-PCC (4F-PCC group) compared to those who did not (no reversal group). Secondary outcomes included functional recovery, hospital and intensive care unit (ICU) length of stay (LOS), and thromboembolic complications.ResultsThere were 62 patients included in the study. Injury Severity Score (ISS) was significantly higher in the 4F-PCC group (17.6 vs. 12.1, p = 0.019). The 4F-PCC group had a significantly higher mortality (22.9% vs. 3.7%, p = 0.034) and longer ICU LOS (2.5 vs. 1.4 days, p = 0.0024). The no reversal group had a significantly higher incidence of ischemic stroke/transient ischemic attack (TIA) (0% vs. 14.8%, p = 0.019). After controlling for ISS, there was no significant difference in mortality (p = 0.20), ICU LOS (p = 0.64), or ischemic stroke/TIA (p = 0.94). There was no difference in hospital LOS, discharge disposition, final Activity Measure for Post Acute Care daily activity score, VTE, or MI.ConclusionPatients with a higher ISS received 4F-PCC preferentially, which led to an apparent mortality benefit the no reversal group. After adjusting for baseline differences between groups, there was no difference in mortality, functional recovery, hospital and ICU LOS, or thromboembolic complications.     

Roles of Four-Factor Prothrombin Complex Concentrate in the Management of Critical Bleeding

Four-factor prothrombin complex concentrate (4F-PCC) is the term used to describe a pathogen-reduced, lyophilized concentrate that contains therapeutic amounts of at least 4 coagulation factors: Factor II (FII), Factor VII (FVII), Factor IX (FIX), and Factor X (FX). 4F-PCC has proven to be an effective hemostatic agent compared to plasma transfusion in several prospective randomized trials in acute warfarin reversal. In recent years, 4F-PCC has been used in various acquired coagulopathies including post-cardiopulmonary bypass bleeding, trauma-induced coagulopathy, coagulopathy in liver failure, and major bleeding due to anti-FXa (anti-Xa) inhibitors (eg, rivaroxaban and apixaban). As transfusion of frozen plasma (FP) has not been found efficacious in the above critical bleeding scenarios, there is increasing interest in expanding the use of 4F-PCC. However, efficacy, safety, and clinical implications of expanded use of 4F-PCC have not been fully elucidated. Prothrombin time and international normalized ratio are commonly used to assess dose effects of 4F-PCC. Prothrombin time/international normalized ratio are standardly use for warfarin titration, but they are not suited for real-time monitoring of complex coagulopathies. Optimal dosing of 4F-PCC outside of the current approved use for vitamin K antagonist reversal is yet to be determined. In this review, we will discuss the use of 4F-PCC in four critical bleeding settings: cardiac surgery, major trauma, end-stage liver disease, and oral anti-Xa reversal. We will discuss recent studies in each area to explore the dosing, efficacy, and safety of 4F-PCC.     

Andexanet alfa for the reversal of anticoagulant activity in patients treated with direct and indirect factor Xa inhibitors

Introduction: Andexanet alfa is a recombinant factor Xa decoy molecule that inhibits direct and indirect factor Xa inhibitors to allow the normal coagulation process to resume. Its development arises in a space where novel oral anticoagulants are receiving expanded indications yet their use is limited by the lack of an effective reversal agent.

Areas covered: This article reviews the biochemical properties, mechanism of action and the preclinical and clinical trials on andexanet alfa. It additionally aims to provide expert commentary and future perspectives on the efficacy, safety and challenges facing andexanet alfa as a universal antidote for direct and indirect factor Xa inhibitors.

Expert commentary: Andexanet alfa shows promise to become a highly effective, novel antidote for factor Xa anticoagulation. Its biochemical profile and mechanism of action are immediately more attractive than other drugs on the market and under development due to its inert nature within the normal coagulation cascade, with minimal intrinsic procoagulant or anticoagulant properties. The anticoagulant antidote space will continue to develop as more specific and universal options become available for reversal of the effect of DOACs. Preliminary results of a pivotal phase 3b/4 trial demonstrate a favorable efficacy and safety profile in patients with acute hemorrhage.     

Prospective Evaluation of a Fixed-Dose 4-Factor Prothrombin Complex Concentrate Protocol for Urgent Vitamin K Antagonist Reversal

BackgroundFour-factor prothrombin complex concentrate (4F-PCC) is the standard of care for reversal of vitamin K antagonists (VKAs). Research has demonstrated noninferior efficacy with the use of lower, fixed-dose strategies for 4F-PCC dosing.ObjectivesWe compared a fixed-dose 4F-PCC protocol to weight-based dosing at our institution.MethodsThis was a multicenter, noninferiority, interventional, quasiexperimental cohort study including subjects who were administered 4F-PCC for VKA reversal. The retrospective cohort consisted of subjects given a weight-based dose of 4F-PCC dependent on international normalized ratio (INR). The prospective cohort was managed with a fixed-dose protocol. The fixed dose was 1500 units of factor IX unless subjects weighed >100 kg or had a baseline INR >7.5, in which case the dose was 2000 units of factor IX. The primary endpoint was achievement of a postinfusion INR of <2. Secondary endpoints included achievement postinfusion INR <1.5, mean 24-h INR, 7-day mortality, and 7-day venous thromboembolic events.ResultsTwenty-four subjects were enrolled in the prospective cohort and 30 in the retrospective cohort. A postinfusion INR <2 was achieved in 96% of subjects in the retrospective cohort and 95% in the prospective cohort (p = 0.0035 for noninferiority). A postinfusion INR <1.5 occurred in 90% of subjects in the retrospective cohort and 75% in the prospective cohort (p > 0.4 for noninferiority). There were no significant differences in 24-h postinfusion INRs, mortality, or venous thromboembolic events.ConclusionThe use of a fixed-dose 4F-PCC protocol is safe and effective for the rapid reversal of VKA-associated anticoagulation.     

Four factor prothrombin complex concentrate (human): review of the pharmacology and clinical application for vitamin K antagonist reversal

Vitamin K antagonists (VKAs) have been used for decades for the treatment and prophylaxis of thromboembolic events. Due to their wide range of therapeutic indications, they are the most prescribed oral anticoagulant worldwide. However, they are associated with bleeding complications due to their narrow therapeutic range, variability in individual dose responses and laboratory monitoring, and overdoses. Despite off-label use of 3-factor prothrombin complex concentrates and recombinant activated factor VII, until recently, vitamin K and plasma were the only recommended therapeutic options for reversing VKAs in the USA. In 2013, a 4-factor prothrombin complex concentrate (4F-PCC) was approved in the USA for VKA reversal in patients with bleeding or requiring emergency surgery and invasive procedure. Recent randomized controlled clinical trials have shown that 4F-PCC (Kcentra?) is non-inferior for hemostatic efficacy and superior for international normalized ratio correction as compared to plasma and has a similar safety profile.     

Current Strategies for the Management of Bleeding Associated with Direct Oral Anticoagulants and a Review of Investigational Reversal Agents

BackgroundThe management of life-threatening bleeding in patients who are receiving direct oral anticoagulants (DOACs) is a serious medical concern.ObjectiveThis review provides a concise, balanced overview of the current and future approaches for reversing the anticoagulation effects of DOACs, particularly factor Xa (FXa) inhibitors.DiscussionThe anticoagulant activity of the direct thrombin inhibitor dabigatran can be reversed by idarucizumab, but until recently, options for the management of major bleeding in patients who were receiving FXa inhibitors were limited to nonspecific strategies, including supplementation of clotting factors with prothrombin complex concentrates (PCCs) or activated PCCs for attenuating anticoagulation effects. They appear as a treatment option in many hospital guidelines despite the lack of approval by the U.S. Food and Drug Administration and the lack of rigorous medical evidence supporting their use in this setting. The development of specific reversal agents may provide improved strategies for the management of bleeding. Andexanet alfa is a modified FXa molecule approved in the United States to reverse the anticoagulant effects of FXa inhibitors (rivaroxaban and apixaban) in patients with life-threatening or uncontrolled bleeding. Ciraparantag is a small-molecule inhibitor of multiple anticoagulants that has been investigated in healthy subjects.ConclusionThe current guidelines for management of DOAC-associated bleeding are being updated to reflect that the reversal agent for rivaroxaban and apixaban is now available. For other FXa inhibitors, in the absence of a reversal agent, nonspecific strategies that include PCCs are recommended. The population of patients anticoagulated with DOACs is growing, and we hope that specific reversal agents will improve the approach to management of major bleeding in this population.     

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.     

A prospective,observational study of Xigris Use in the United States (XEUS)

BackgroundUse of pharmacologic agents in clinical practice may differ from the manner in which they were studied in rigorous randomized clinical trials. This was a prospective, observational, noninterventional study to determine the profile of patients receiving drotrecogin alfa (activated) in clinical practice, provide additional outcome and safety data, and allow for a comparison to patients studied in the phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial.MethodsA total of 548 adult patients with severe sepsis were enrolled from 61 nonteaching or academically affiliated hospitals in the United States. Patients received drotrecogin alfa (activated) as part of physician-directed therapy for severe sepsis.ResultsThe Xigris Use in the United States (XEUS) patients were younger (58 vs 63 years of age), had more comorbidities, and more sepsis-induced organ dysfunction at baseline compared to high-risk (Acute Physiology and Chronic Health Evaluation II score ≥ 25) PROWESS patients who received drotrecogin alfa (activated), (cardiovascular, 85.0% vs 79.7%; hematologic, 22.3% vs 16.4%; and renal, 57.9% vs 50.7%) (all P < .05). The XEUS patients had a higher mortality rate compared to high-risk PROWESS patients receiving drotrecogin alfa (activated) (36.7% vs 30.9%; P = .062) but a similar safety profile (infusion period serious bleeding, 2.7% vs 2.2%; P = .579; 28-day serious bleeding, 3.1% vs 3.9%; P = .520). The rate of intracranial hemorrhage in XEUS was 0.2%.ConclusionsPatients receiving drotrecogin alfa (activated) in clinical practice were more acutely ill, had a higher mortality rate, but a similar safety profile with respect to serious bleeding events compared to the PROWESS trial.     

Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis

OBJECTIVE: To assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]). DESIGN: Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study. SETTING: A total of 164 medical centers in 11 countries. PATIENTS: A total of 1,690 patients with severe sepsis. MEASUREMENTS AND MAIN RESULTS: We report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a > or = 20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality. CONCLUSIONS: The administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.     

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 safety of oral anticoagulants registry (SOAR): A national,ED-based study of the evaluation and management of bleeding and bleeding concerns due to the use of oral anticoagulants

ObjectiveThe Safety of Oral Anticoagulants Registry (SOAR) was designed to describe the evaluation and management of patients with oral anticoagulant (OAC)-related major bleeding or bleeding concerns who present to the emergency department (ED) with acute illness or injury. Patients in the ED are increasingly taking anticoagulants, which can cause bleeding-related complications as well as impact the acute management of related or unrelated clinical issues that prompt presentation. Modifications of emergency evaluation and management due to anticoagulation have not previously been studied.MethodsThis was a multicenter observational in-hospital study of patients who were judged to be experiencing an active OAC effect and had (a) an obvious bleeding event or (b) were deemed at risk for serious bleeding spontaneously, after injury, or during an indicated invasive procedure. Diagnostic testing, therapies employed, and clinical outcomes were collected.ResultsThirty-one US hospitals contributed data to SOAR. Of 1513 subjects, acute hemorrhage (AH) qualified 78%, while 22% had a bleeding concern (BC). Warfarin was the index OAC in 37.3%, dabigatran in 13.3%, and an anti-Factor X_a in 49.4%. The most common sites of AH were gastrointestinal (51.0%) and intracranial (26.8%). In warfarin-treated patients, the mean (IQR) presenting INR was 3.1 (2.2, 4.8) in AH patients and 3.9 (2.4, 7.2) in BC patients. Three-fifths of SOAR patients were treated with factor repletion or specific reversal agents, and those patients had a longer length of stay. In addition, seven (0.76%) of the treated patients experienced an in-hospital thrombotic complication; two of these seven died on the index admission, both of fatal pulmonary embolism. Vitamin K was used and dosed inconsistently in both warfarin and NOAC cohorts.ConclusionCare of anticoagulated patients in the acute care setting is inconsistent, reflecting the diversity of presentation. As the prevalence of OAC use increases with the aging of the US population, further study and targeted educational efforts are needed to drive more evidence-based care of these patients.     

Clinical significance of thrombocytopenia in patients with septic shock: An observational retrospective study

PurposeWhether thrombocytopenia in critically ill patients accounts for a bystander of severity or drives specific complications is unclear. We addressed the effect of thrombocytopenia on septic shock, with emphasis on intensive care unit (ICU)-acquired bleeding, infections and thrombotic complications.Materials and methodsA retrospective (2008–2019) single-center study of patients with septic shock. Thrombocytopenia was assessed over the first seven days and was defined as severe (nadir <50 G/L), mild (nadir 50–150 G/L) and relative (30% decrease with nadir >150 G/L). Outcomes were ICU mortality and ICU-acquired complications defined by severe bleeding, infections and thrombotic events during the ICU stay.ResultsThe study comprised 1024 patients. Severe, mild and relative thrombocytopenia occurred in 33%, 40% and 9% of patients. The in-ICU mortality rate was 27%, independently associated with severe thrombocytopenia. ICU-acquired infections, hemorrhagic and thrombotic complications occurred in 27.5%, 13.3% and 11.6% of patients, respectively. Patients with severe, mild or relative thrombocytopenia exhibited higher incidences of bleeding events (20.3%, 15.3% and 14.4% vs. 3.6% in non-thrombocytopenic, p < 0.001), infections (35.2%, 21.9% and 33.3% vs. 23.1% in non-thrombocytopenic, p < 0.001) and thrombotic events (14.6%, 10.8% and 17.8% vs. 7.8% in non-thrombocytopenic, p = 0.03). Only severe thrombocytopenia remained independently associated with increased risk of bleeding.ConclusionsSevere thrombocytopenia was independently associated with ICU mortality and increased risk of bleeding, but not with infectious and thrombotic events.     

The Perioperative Management of Patients With Left Ventricular Assist Devices Undergoing Noncardiac Surgery

ObjectiveTo describe the perioperative management of patients with left ventricular assist devices (LVADs) who require general anesthesia while undergoing noncardiac surgery (NCS) at a single, large tertiary referral center.Patients and MethodsElectronic medical records from September 2, 2005, through May 31, 2012, were retrospectively reviewed to evaluate the perioperative management and outcomes in LVAD patients undergoing NCS. Patients were included only if they required a general anesthetic and had previously been discharged from the hospital after initial LVAD implantation.ResultsThirty-three patients with LVADs underwent general anesthesia for 67 noncardiac operations. The mean ± SD time from LVAD implantation to NCS was 317±349 days. All but 1 patient had axial flow LVADs. Anticoagulation or antiplatelet agents were present within 7 days before NCS in 49 procedures (73%) and reversed in 32 of 49 (65%). No perioperative thrombotic complications related to anticoagulation or antiplatelet reversal were noted. Red blood cell, fresh frozen plasma, and platelet transfusions were administered during 10, 6, and 4 operations, respectively. The only intraoperative complication was surgical bleeding. Postoperative complications were present in 12 patients after NCS and were mainly composed of bleeding. Three patients died within 30 days of NCS, with the causes of death not attributed to NCS.ConclusionPatients with LVAD safely underwent NCS in a multidisciplinary setting that included preoperative optimization by cardiologists familiar with LVADs when feasible. Anticoagulation or antiplatelet agents were present preoperatively in most patients with LVADs and were safely reversed when necessary for NCS. The relatively high occurrence of postoperative bleeding is consistent with previous series.