Multicenter evaluation of left ventricular assist device implantation with or without ECMO bridge in cardiogenic shock.

BACKGROUND: The efficacy of extracorporeal membrane oxygenation (ECMO) as a bridge to left ventricular assist device (LVAD) remains unclear, and recipients of the more contemporary HeartMate 3 (HM3) LVAD are not well represented in previous studies. We therefore undertook a multicenter, retrospective study of this population. METHODS AND RESULTS: INTERMACS 1 LVAD recipients from five U.S. centers were included. In-hospital and one-year outcomes were recorded. The primary outcome was the overall mortality hazard comparing ECMO versus non-ECMO patients by propensity-weighted survival analysis. Secondary outcomes included survival by LVAD type, as well as postoperative and one-year outcomes. One hundred and twenty-seven patients were included; 24 received ECMO as a bridge to LVAD. Mortality was higher in patients bridged with ECMO in the primary analysis (HR 3.22 [95%CI 1.06-9.77], p = 0.039). Right ventricular assist device was more common in the ECMO group (ECMO: 54.2% vs non-ECMO: 11.7%, p < 0.001). Ischemic stroke was higher at one year in the ECMO group (ECMO: 25.0% vs non-ECMO: 4.9%, p = 0.006). Among the study cohort, one-year mortality was lower in HM3 than in HeartMate II (HMII) or HeartWare HVAD (10.5% vs 46.9% vs 31.6%, respectively; p < 0.001) recipients. Pump thrombosis at one year was lower in HM3 than in HMII or HVAD (1.8% vs 16.1% vs 16.2%, respectively; p = 0.026) recipients. CONCLUSIONS: Higher mortality was observed with ECMO as a bridge to LVAD, likely due to higher acuity illness, yet acceptable one-year survival was seen compared with historical rates. The receipt of the HM3 was associated with improved survival compared with older generation devices.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study.

BACKGROUND: Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. OBJECTIVES: This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. METHODS: Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. RESULTS: In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). CONCLUSION: Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

Impact of as needed heparin boluses on supratherapeutic activated partial thromboplastin time in patients managed with extracorporeal membrane oxygenation.

INTRODUCTION: Brigham and Women's Hospital (BWH) historically used titratable weight-based heparin nomograms with as needed boluses managed by extracorporeal membrane oxygenation (ECMO) specialists to achieve a pre-determined goal activated partial thromboplastin time (aPTT). Due to concern amongst providers that as needed boluses may lead to supratherapeutic aPTT's and subsequent bleeding, new nomograms without as needed boluses were implemented. The purpose of this retrospective observational analysis is to provide a comparison in safety and efficacy between the heparin nomograms with as needed boluses and the new nomograms without boluses. METHODS: Adult patients who were cannulated on ECMO and initiated on an approved heparin bolus nomogram (January 1, 2018-December 31, 2019) or an approved heparin no bolus nomogram (October 20, 2020-March 31, 2021) were screened for inclusion. The major endpoint evaluated was the percentage of supratherapeutic aPTTs, defined as an aPTT above the upper limit of the specified nomogram goal, within the first 72 hours. RESULTS: A total of 23 patients were included in the bolus nomogram cohort and 9 patients in the no-bolus nomogram cohort. Within the first 72 hours of initiation, there were 11.5% supratherapeutic aPTTs in the bolus group and 5.1% in the no-bolus group (p=0.101). Overall there was one bleeding event in the no-bolus group (11.1%) and seven in the bolus group (30.4%) (p=0.26). There were no thromboembolic events in either group. CONCLUSION: Overall, there was no difference found in percentage of supratherapeutic aPTTs within the first 72 hours of heparin initation between the bolus and no-bolus nomograms.

One-year retrospective analysis of anti-FXa apixaban and rivaroxaban levels demonstrates utility for management decisions in various urgent and nonurgent clinical situations.

OBJECTIVES: Quantification of direct oral anticoagulant (DOAC) plasma levels can guide clinical management, but insight into clinical scenarios surrounding DOAC-calibrated anti-FXa assays is limited. METHODS: Apixaban- and rivaroxaban-calibrated chromogenic anti-Xa assays performed over a 1-year period were retrospectively analyzed. Patient demographics, DOAC history, concomitant medications, and renal/liver comorbidities were obtained. Indications for testing and associated clinical actions were reviewed. Machine learning (ML) models predicting clinical actions were evaluated. RESULTS: In total, 371 anti-FXa apixaban and 89 anti-FXa rivaroxaban tests were performed for 259 and 67 patients in recurring urgent (acute bleeding, unplanned procedures) and nonurgent situations, including several scenarios not captured by existing testing recommendations (eg, drug monitoring, recurrent thromboembolic events, bleeding tendency). In urgent settings, andexanet reversal was guided by radiologic and clinical findings over DOAC levels in 14 of 32 instances, while 51% of apixaban patients qualified for nonreversal strategies through the availability of levels. Levels also informed procedure/intervention timing and supported management decisions when DOAC clearance or DOAC target levels were in question. The importance of clinical context was emphasized by exploratory ML models predicting particular clinical actions. CONCLUSIONS: Although clinical situations are complex, DOAC testing facilitates clinical decision-making, including reversal, justifying more widespread implementation of these assays.

Anticoagulation-Associated Adverse Drug Events in Hospitalized Patients Across Two Time Periods.

PURPOSE: Anticoagulants often cause adverse drug events (ADEs), comprised of medication errors and adverse drug reactions, in patients. Our study objective was to determine the clinical characteristics, types, severity, cause, and outcomes of anticoagulation-associated ADEs from 2015-2020 (a contemporary period following implementation of an electronic health record, infusion device technology, and anticoagulant dosing nomograms) and to compare them with those of a historical period (2004-2009). METHODS: We reviewed all anticoagulant-associated ADEs reported as part of our hospital-wide safety system. Reviewers classified type, severity, root cause, and outcomes for each ADE according to standard definitions. Reviewers also assessed events for patient harm. Patients were followed up to 30 days after the event. RESULTS: Despite implementation of enhanced patient safety technology and procedure, ADEs increased in the contemporary period. In the contemporary period, we found 925 patients who had 984 anticoagulation-associated ADEs, including 811 isolated medication errors (82.4%); 13 isolated adverse drug reactions (1.4%); and 160 combined medication errors, adverse drug reactions, or both (16.2%). Unfractionated heparin was the most frequent ADE-related anticoagulant (77.7%, contemporary period vs 58.3%, historical period). The most frequent anticoagulation-associated medication error in the contemporary period was wrong rate or frequency of administration (26.1%, n = 253), with the most frequent root cause being prescribing errors (21.3%, n = 207). The type, root cause, and harm from ADEs were similar between periods. CONCLUSIONS: We found that anticoagulation-associated ADEs occurred despite advances in patient safety technologies and practices. Events were common, suggesting marginal improvements in anticoagulant safety over time and ample opportunities for improvement.

Evaluation of the use of direct oral anticoagulants for the management of heparin-induced thrombocytopenia.

Historically, treatment of heparin-induced thrombocytopenia (HIT) includes a non-heparin parenteral anticoagulant with bridging to warfarin once platelets recover. Data supporting the use of direct oral anticoagulants (DOACs) for HIT treatment are limited. Given the paucity of evidence for the use of DOACs in HIT, the aim of this study is to describe the prescribing patterns of DOACs for HIT at our institution. This is a single center, retrospective chart evaluation of patients admitted from January 2017 to October 2020 with a confirmed diagnosis of HIT. Twenty-six patients were identified; 21 patients (81%) received initial parenteral treatment and 5 patients (19.2%) with initial DOAC treatment. The most frequently used DOAC was apixaban at the VTE treatment dose [15 (57.7%)] followed by the reduced dose of apixaban [5 (19.2%)]. Of the patients initially treated with a parenteral agent, 11 (42.3%) were transitioned to a DOAC after platelet recovery, 7 (26.9%) transitioned as platelets were steadily increasing, and 3 (11.5%) transitioned at the time of discharge (prior to platelet recovery). Platelet recovery was achieved in 23 patients (88.5%) at a median of 5 days (IQR 2.8-8.3) after HIT diagnosis. No new thrombotic or bleeding events occurred within 30 days of HIT diagnosis. In our patients treated with a DOAC for HIT, no progression of HIT was observed. Apixaban was the most frequently utilized DOAC. Most patients received a parenteral anticoagulant prior to DOAC initiation. All patients managed with a DOAC as initial treatment achieved platelet recovery within 30 days of HIT diagnosis.

A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation.

Direct-acting oral anticoagulant (DOAC) use has increased dramatically since their introduction because of the growing evidence of proven efficacy and enhanced safety compared with warfarin and the low-molecular-weight heparins in the general population. Unfortunately, there is a dearth of quality data regarding the safety and efficacy of the DOACs in patients awaiting organ transplant and those who received a solid organ transplant. This review aims to evaluate the available literature and considerations regarding anticoagulation use in transplant recipients, focusing on preoperative, perioperative, and postoperative DOAC use.

Optimization of DOAC management services in a centralized anticoagulation clinic.

Background: In 2017, the Brigham and Women's Hospital Anticoagulation Management Service (BWH AMS) expanded services to patients on direct oral anticoagulants (DOACs). We have since updated our DOAC management plan and adjusted the workflow of our clinic. Objectives: This report describes how our DOAC management has evolved and describes key interventions made. Additionally, we report on the results of a survey completed by referring physicians that assessed perspectives regarding centralized DOAC management by BWH AMS pharmacists. Methods: An analysis was completed of all patients referred to the BWH AMS and the number of interventions completed and documented in our anticoagulation management software. A survey with eight questions was sent to 110 referring physicians (selected based on referring to the AMS within the past 1.5 years). Results: Over 4 years, 1622 patients on DOACs were referred to the BWH AMS, amounting to 3154 DOAC encounters. A total of 212 interventions for medication procurement, 171 dose adjustment interventions, and 603 coordinated procedure plans were completed. Of the 32 physicians who responded to the survey, many believed that the quality and safety of anticoagulation therapy was improved with BWH AMS management. Despite provider satisfaction with pharmacist-led care in DOACs, physicians expressed concerns regarding the lack of provider awareness of the clinic and possible duplicative efforts. Conclusion: We plan to evolve the DOAC clinic model to optimize its clinical and operational value and to improve our delivery of care using electronic tools to move toward a population management approach for DOAC management.

Activated Clotting Times Demonstrate Weak Correlation With Heparin Dosing in Adult Extracorporeal Membrane Oxygenation.

BACKGROUND: The optimal monitoring strategy for anticoagulation management in extracorporeal membrane oxygenation (ECMO) remains a clinical controversy. The Extracorporeal Life Support Organization Anticoagulation Guidelines suggest that multiple anticoagulation assays may be needed but do not specify a preferred management strategy. STUDY QUESTION: In adult ECMO patients, which anticoagulation assays demonstrate the highest correlation with unfractionated heparin (UFH) dose requirements? STUDY DESIGN: We performed a retrospective chart review of adult patients cannulated to ECMO between February 2013 and July 2015. MEASURES AND OUTCOMES: The primary outcome was the correlation between activated clotting time (ACT), activated partial thromboplastin time (aPTT), and anti-Xa and UFH dose. Secondary outcomes included correlations between anticoagulation assays. Correlations were calculated for the entire cohort, with subgroup analysis of venoarterial and venovenous ECMO patients. RESULTS: Forty-eight patients were included in the analysis, 26 initially cannulated to venoarterial ECMO and 22 to veno-venous ECMO. The median duration of ECMO therapy was 7 days. Mean UFH requirements were 1149 units/h or 15.3 units/kg/h. Total UFH dose was most correlated with anti-Xa levels (r = 0.467), whereas weight-based heparin dose was most correlated with aPTT (0.405). For correlations between anticoagulation assays, anti-Xa and aPTT were more highly correlated with each other (r = 0.633) compared with ACT. CONCLUSIONS: In adult patients requiring ECMO, anti-Xa and aPTT monitoring were correlated more closely with UFH dosing than ACT.

Heparin-induced thrombocytopenia in end-stage renal disease: Reliability of the PF4-heparin ELISA.

BACKGROUND: Diagnosing heparin-induced thrombocytopenia (HIT) in patients with end-stage renal disease (ESRD) can be difficult, as they are frequently exposed to heparin and have multiple etiologies for thrombocytopenia. OBJECTIVE: To correlate 4T scores, IgG heparin-platelet factor 4 (PF4-heparin) ELISA results, and serotonin release assay (SRA) results in patients with ESRD. METHODS: We performed a retrospective review of patients with ESRD (creatinine clearance < 15 mL/min or on renal replacement therapy [RRT]) who underwent PF4-heparin ELISA testing from October 2015 to September 2019. True-positive PF4s required an intermediate to high 4T score (≥4), a positive SRA, and receipt of treatment for a HIT diagnosis. False-positive PF4s were defined as a positive PF4 with a negative SRA, low 4T score (<4), or lack of treatment for HIT. Indeterminant cases were classified on the basis of clinical assessment by the treating team (eg, hematology or vascular medicine). RESULTS: Of 254 patients with ESRD (92% on RRT), 29 patients (11.4%) had a positive PF4. Eleven (37.9%) had a confirmed diagnosis of HIT: 10 patients who met all of the above criteria, and one who met the 4T criteria and was treated for HIT but did not have SRA testing due to high clinical suspicion and a positive PF4 test. False-positive PF4 values occurred in 8 patients (27.5%). Of 10 (34.5%) indeterminant cases of patients with a negative SRA but intermediate to high 4T and positive PF4, only 3 patients were treated for HIT, whereas the other 7 were judged not to have HIT as assessed by the treating clinician. In patients with an intermediate to high 4T score and PF4 optical density > 0.4 but negative SRA, who were not treated for HIT, there were no adverse outcomes documented such as new or progressive thrombosis. CONCLUSION: In our ESRD population, 4T scores and PF4 testing were not predictive of a clinical diagnosis of HIT.

Management of therapeutic unfractionated heparin in COVID-19 patients: A retrospective cohort study.

BACKGROUND: Patients hospitalized with severe acute respiratory syndrome coronavirus 2 infection are at risk for thrombotic complications necessitating use of therapeutic unfractionated heparin (UFH). Full-dose anticoagulation limits requirements for organ support interventions in moderately ill patients with coronavirus disease 2019 (COVID-19). Given this benefit, it is important to evaluate response to therapeutic anticoagulation in this population. OBJECTIVES: The aim of this study was to assess therapeutic UFH infusions and associated bleeding risk in patients with COVID-19. PATIENTS/METHODS: This retrospective cohort study includes patients at Brigham and Women's Hospital, Boston, Massachusetts, receiving weight-based nursing-nomogram titrated UFH infusion during a 10-week surge in COVID-19 hospitalizations. Of 358 patients on therapeutic UFH during this interval, 97 (27.1%) had confirmed COVID-19. Patient characteristics, laboratory values, and information regarding UFH infusion and bleeding events were obtained from the electronic medical record. RESULTS: Patients who were COVID-19 positive had fewer therapeutic activatrd partial thromboplastin times (aPTTs) compared to COVID-19-negative patients (median rate, 40.0% vs 53.1%; P < .0005). Both major and clinically relevant nonmajor bleeding were increased in COVID-19-positive patients, with major bleeding observed in 10.3% (95% confidence interval [CI], 5.7%-17.9%) of patients who were COVID-19 positive and 3.1% (95% CI, 1.6%-5.9%) of patients who were COVID-19 negative (P < .005). In logistic regression, bleeding events were associated with receiving UFH for longer than 7 days, but not platelet count, coagulation, or inflammatory measurements. CONCLUSIONS: Our data indicate a higher incidence of bleeding complications in patients with COVID-19 receiving weight-based nursing-nomogram titrated UFH infusions despite a higher prevalence of subtherapeutic aPTTs in this population. These data underscore the need for prospective studies aimed at improving the quality and safety of therapeutic anticoagulation in patients with COVID-19.

Extended duration venous thromboembolism prophylaxis with betrixaban for patients re-admitted with venous thromboembolism.

Patients hospitalized for an acute medical illness remain at risk of developing venous thromboembolism (VTE) post-discharge. Betrixaban, an oral direct Factor Xa inhibitor, is approved for extended VTE thromboprophylaxis in acutely ill medical patients. The primary objective of this study was to evaluate patients re-admitted with VTE within 30 days of discharge to determine if they would have been eligible for extended duration VTE prophylaxis during the index admission. We used three different sets of eligibility criteria: the APEX study criteria, the Bevyxxa® (betrixaban) package insert, and Mass General Brigham HealthCare System's Center for Drug Policy Guidelines. A secondary aim was to describe the reasons for ineligibility. Within 30 days of the index hospital admission, 226 patients were re-admitted with new VTE between January 2017 and December 2018. Of these, 134 (59%) were excluded based on pre-defined exclusion criteria. Of the remaining 92, 22 patients (23.9%) were eligible based on the APEX study criteria, 26 patients (28.2%) based on Mass General Brigham HealthCare System's Center for Drug Policy Guidelines, and 92 patients (100%) based on the Bevyxxa® package insert. There were 22 patients (23.9%) who were eligible for VTE prophylaxis with betrixaban based on all three criteria. Appropriate betrixaban use may have prevented some of the VTE events and re-admissions that occurred within 30 days of initial hospital discharge.

Evaluation and optimization of prescribed concomitant antiplatelet and anticoagulation therapy centrally managed by an anticoagulation management service.

Patients on long-term anticoagulation combined with antiplatelet therapy have an increased risk of bleeding compared to patients on anticoagulation alone. The aim of this study was to evaluate the appropriateness of antiplatelet therapy in patients who are on long-term warfarin therapy and are managed by Brigham and Women's Hospital Anticoagulation Management Service (BWH AMS). This was a single-center, prospective chart review of patients managed by BWH AMS who were on long-term warfarin therapy plus full-dose aspirin (325 mg), an oral P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) and/or acetylsalicylic acid/dipyridamole. Patients' cardiovascular (CV) benefit and risk of bleeding were assessed according to clinical guidelines. The major objective of the study was to determine the proportion of patients on dual antithrombotic therapy (DAT) or triple antithrombotic therapy (TAT) whose risk of bleeding outweighed CV benefit. Of the 2677 patients evaluated for inclusion,145 were on concomitant long-term warfarin therapy plus aspirin (325 mg), an oral P2Y12 inhibitor and/or acetylsalicylic acid/dipyridamole. A total of 85 patients (58.6%) had no clear indication for DAT or TAT per guideline recommendations and were categorized as bleeding risk outweighing CV benefit. The remaining 60 patients (41.4%) had an appropriate indication for DAT or TAT per guidelines and were categorized as CV benefit outweighing bleeding risk. BWH AMS pharmacists made 33 (22.9%) recommendations to providers to discontinue or de-escalate antiplatelet therapy. Interventions were accepted for 10 (30.3%) patients. Pharmacist involvement in the management of patients' antithrombotic regimens can optimize guideline-directed medical therapy and mitigate the potential risk of bleeding.

Atrial Fibrillation Patients on Warfarin and Their Transition to Direct Oral Anticoagulants.

BACKGROUND: The standard of care for stroke prevention in nonvalvular atrial fibrillation (AF) is the use of direct oral anticoagulants (DOACs). However, many patients established on warfarin therapy have not been considered for a transition to a DOAC. OBJECTIVES: Assess the AF patient population of Brigham and Women's Hospital (BWH) Anticoagulation Management Service (AMS) currently being treated with warfarin, transition eligible patients to a DOAC, and identify barriers to the transitional process. METHODS: Patient characteristics were analyzed to describe the overall AF population and a systematic process was used to determine clinical candidacy for a transition from warfarin to a DOAC. After being deemed eligible by both the referring physician and the AMS pharmacist, each patient was contacted and offered the opportunity for DOAC transition. Endpoints included number of successful transitions and commonly encountered barriers. RESULTS: Out of the 1407 total AF patients on warfarin managed by BWH AMS, there were 787 patients identified as candidates for DOAC transition and a successful transition was completed for 250 (31.8%) of them. Barriers to transition included patient preference for warfarin (n = 247, 31.4%), referring physician preference for warfarin (n = 112, 14.2%), cost (n = 88, 11.2%), AMS pharmacist preference for warfarin (n = 70, 8.9%), and previous DOAC intolerance (n = 20, 2.5%). CONCLUSIONS: Every institution or provider network that manages AF patients on warfarin should assess their population on a regular basis to identify candidates for DOAC therapy. Our initiative outlines a process for identifying and transitioning DOAC-eligible AF patients established on warfarin therapy and describes the most commonly encountered barriers to DOAC therapy.

Development of an Institutional Periprocedural Management Guideline for Oral Anticoagulants.

Patients on oral anticoagulation commonly undergo surgery or other invasive procedures. Periprocedural management of oral anticoagulants involves a careful balance of the thromboembolic risk and bleeding risk. To standardize clinical practice at our institution, we developed a guideline for periprocedural management for patients taking oral anticoagulants that incorporates published data and expert opinion. In this article, we present our clinical practice guideline as a decision support tool to aid clinicians in developing a consistent strategy for managing periprocedural anticoagulation and for safely bridging anticoagulation in patients who require it.

Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients.

In patients with ischemic stroke who receive systemic recombinant tissue plasminogen activator (rt-PA), the risk of secondary hemorrhage is 1-7%. Fibrinogen supplementation with cryoprecipitate is recommended in patients with rt-PA-associated symptomatic hemorrhage. We examined whether fibrinogen concentrate can be used safely in this setting. A single-center retrospective case series was performed in patients who received fibrinogen concentrate for post-rt-PA hemorrhage between January-2012 and December-2017. The primary outcome was the incidence of in-hospital thromboembolic events and infusion reactions. Secondary outcomes included incidence of clinically significant ICH expansion within 24-hours and patient serum fibrinogen response to fibrinogen concentrate therapy. Thromboembolic events occurred in 3 (12.5%) of 24 patients included in the analysis. No patients experienced infusion-related reactions. Five of 22 patients with ICH experienced clinically significant hemorrhage expansion. Hypofibrinogenemia was corrected in 87.5%(7/8) of patients with baseline hypofibrinogenemia, with a median increase in serum fibrinogen 166 mg/dL. Median fibrinogen increase in patients without baseline hypofibrinogenemia was 18 mg/dL. Fibrinogen concentrate is a safe potential therapeutic option to restore fibrinogen levels in acute ischemic stroke patients with thrombolysis-associated hemorrhage.