Temporarily Reversing Warfarin With Low-Dose 4-Factor Prothrombin Complex Concentrate in Left Ventricular Assist Device Patients Undergoing an Invasive Procedure.

BACKGROUND: American Association for Thoracic Surgery and The International Society for Heart and Lung Transplantation (AATS/ISHLT) guidelines recommend warfarin in patients with continuous-flow left ventricular assist devices (LVADs) to reduce the risk of device thrombosis and systemic embolization. Left ventricular assist device patients often undergo elective and emergent procedures that require interrupted anticoagulation. Data and experience vary on the optimal strategy to rapidly reverse warfarin in LVAD patients when an emergent procedure is planned. OBJECTIVE: The purpose of this study was to describe the use of 4-factor prothrombin complex concentrate (PCC4) for warfarin reversal in patients with LVADs undergoing elective and emergent procedures. METHODS: This retrospective, single-center, cohort review describes the use of PCC4 in patients with LVADs who require warfarin reversal for elective or emergent procedures. The primary outcome was a composite incidence of pump thrombosis, venous thromboembolism, and ischemic stroke within 30 days of PCC4 administration. RESULTS: In total, 14 patients received 17 administrations of PCC4. One patient received 3 administrations, and 1 other patient received 2 administrations during separate encounters. The median dose was 500 units or 6.6 units/kg (range = 4.2-14.1 units/kg). Of the PCC4 administrations, 82% (14/17) were for low bleed risk procedures and 76% (13/17) were for elective procedures. There were no cases of pump thrombosis, venous thromboembolism, or stroke within 30 days of the procedure. CONCLUSIONS AND RELEVANCE: Low-dose PCC4 appears to be a safe and effective temporary reversal strategy for patients with LVADs undergoing low-bleed risk elective procedures.

Approaches to Precision-based Anticoagulation management in the critically Ill.

Anticoagulant therapy is commonly associated with a high incidence of avoidable adverse events, especially in the acute care setting. This has led to several initiatives by key national health care stakeholders, including specific attention to The Joint Commission's National Patient Safety Goals, to improve anticoagulation management. The subject of special populations has long been identified as challenging by clinicians with the use of anticoagulants. This is driven in part by numerous variables that can contribute to hard outcomes such as bleeding, thrombosis, length of stay, hospital re-admission, morbidity, and mortality. Despite the notable effort to improve the use of anticoagulants with numerous clinical trials, guidelines, guidance statements, and other sources of published evidence, notable difficulties continue to challenge practitioners in managing this class of medications. This is especially the case with very diverse critically ill populations where countless variables exist, many of which were never explored in trials or have historically been frequently excluded. Trials evaluating anticoagulation therapy often can only account for small portions of variables that may affect thrombosis and hemostasis, and study methods often do not reflect the constantly changing dynamic conditions seen in unique critically ill patients. Clinicians providing care to the numerous critically ill populations are faced with conditions that lead to relatively small therapeutic windows, which makes designing safe optimal anticoagulation management plans difficult when dealing with complex patients and mechanical support devices. The approach to crafting a successful management plan for anticoagulant therapy must incorporate the numerous variables that are continuously assessed and revised during the patient's time in the intensive care unit. We explore considerations and approaches when developing, assessing, and implementing an individualized or precision-based management plan that involves the use of anticoagulants in the critically ill. The skills and thought process provided will assist clinicians in managing this unique, variable, and challenging population.

Perioperative management of antithrombotic therapy: an American college of chest physicians clinical practice guideline

The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug. Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines. A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures. Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management

Positive Patient Postoperative Outcomes with Pharmacotherapy: A Narrative Review including Perioperative-Specialty Pharmacist Interviews.

The influence of pharmacotherapy regimens on surgical patient outcomes is increasingly appreciated in the era of enhanced recovery protocols and institutional focus on reducing postoperative complications. Specifics related to medication selection, dosing, frequency of administration, and duration of therapy are evolving to optimize pharmacotherapeutic regimens for many enhanced recovery protocolized elements. This review provides a summary of recent pharmacotherapeutic strategies, including those configured within electronic health record (EHR) applications and functionalities, that are associated with the minimization of the frequency and severity of postoperative complications (POCs), shortened hospital length of stay (LOS), reduced readmission rates, and cost or revenue impacts. Further, it will highlight preventive pharmacotherapy regimens that are correlated with improved patient preparation, especially those related to surgical site infection (SSI), venous thromboembolism (VTE), nausea and vomiting (PONV), postoperative ileus (POI), and emergence delirium (PoD) as well as less commonly encountered POCs such as acute kidney injury (AKI) and atrial fibrillation (AF). The importance of interprofessional collaboration in all periprocedural phases, focusing on medication management through shared responsibilities for drug therapy outcomes, will be emphasized. Finally, examples of collaborative care through shared mental models of drug stewardship and non-medical practice agreements to improve operative throughput, reduce operative stress, and increase patient satisfaction are illustrated.

Executive Summary: Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline.

BACKGROUND: The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug. METHODS: Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines. RESULTS: A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures. CONCLUSIONS: Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management questions.

Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline.

BACKGROUND: The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug. METHODS: Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines. RESULTS: A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures. CONCLUSIONS: Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management questions.

Comparison of Managing Factor Xa Inhibitor to Unfractionated Heparin Transitions by aPTT Versus a Treatment Guideline Utilizing Heparin Anti-Xa Levels.

BACKGROUND: There are inadequate data on the optimal strategy for transitioning factor Xa inhibitors (FXai; apixaban, rivaroxaban) to unfractionated heparin (UFH) infusions. OBJECTIVE: In patients transitioning from an FXai to an UFH infusion, this study compared the safety and efficacy of monitoring UFH infusions using an activated partial thromboplastin time (aPTT) titration scale versus utilizing an UFH-calibrated anti-Xa titration scale aided by a novel institutional guideline. METHODS: A retrospective cohort analysis was conducted on adult patients transitioning from an FXai to an UFH infusion at 2 medical centers from June 1, 2018, to November 1, 2020. One institution utilized aPTT while the other institution primarily used UFH-calibrated anti-Xa. The primary endpoint was a composite of death, major bleeding, or new thrombosis during the hospitalization with a planned noninferiority analysis. Secondary outcomes were also collected including the amount and duration of UFH administered between cohorts. RESULTS: The incidence rate of the primary composite endpoint was 6.3% in the anti-Xa group and 11% in the aPTT group (P < 0.001 for noninferiority, P = 0.138 for superiority) meeting noninferiority criteria. No statistical differences were seen in new thrombosis, major bleeding, or any bleeding. CONCLUSION AND RELEVANCE: This represents the first report of a comparison between aPTT versus anti-Xa monitoring in relation to clinical outcomes for patients transitioning from an FXai to an UFH infusion. A transition guideline primarily utilizing an UFH-calibrated anti-Xa assay appears to be a safe alternative to aPTT monitoring and can aid facilities in the management of patients during these complex transitions.

Thromboembolic prevention and anticoagulant therapy during the COVID-19 pandemic: updated clinical guidance from the anticoagulation forum.

Thromboembolism is a common and deadly consequence of COVID-19 infection for hospitalized patients. Based on clinical evidence pre-dating the COVID-19 pandemic and early observational reports, expert consensus and guidance documents have strongly encouraged the use of prophylactic anticoagulation for patients hospitalized for COVID-19 infection. More recently, multiple clinical trials and larger observational studies have provided evidence for tailoring the approach to thromboprophylaxis for patients with COVID-19. This document provides updated guidance for the use of anticoagulant therapies in patients with COVID-19 from the Anticoagulation Forum, the leading North American organization of anticoagulation providers. We discuss ambulatory, in-hospital, and post-hospital thromboprophylaxis strategies as well as provide guidance for patients with thrombotic conditions who are considering COVID-19 vaccination.

Activated Partial Thromboplastin Time Versus Anti-Factor Xa Monitoring of Heparin Anticoagulation in Adult Venoarterial Extracorporeal Membrane Oxygenation Patients.

The preferred assay for measuring and adjusting unfractionated heparin (UFH) infusion to achieve optimal outcomes during extracorporeal membrane oxygenation (ECMO) is not well established. This retrospective cohort study explored safety and efficacy outcome differences between anti-factor Xa (anti-Xa) and activated partial thromboplastin time (aPTT) for UFH in adult venoarterial ECMO. Forty-one patients were included and analyzed. The UFH rate at first goal and time to goal were both higher in the aPTT versus anti-Xa cohort but did not achieve statistical significance (12.14 vs. 9.58 unit/kg/hour (p = 0.29), 20.22 vs. 12.05 hours (p = 0.11)). The aPTT cohort was in target goals 35.0% of the time versus 47.7% in the anti-Xa cohort (p = 0.13), above goal 41.0% vs. 17.3% (p = 0.02), and below-goal 24.0% versus 35.0% of the time (p = 0.34). Minimum heparin rates in the aPTT cohort were 6.28 vs. 3.33 unit/kg/hour in the anti-Xa cohort (p = 0.07), and the maximum UFH rate was 18.77 unit/kg/hour vs. 15.48 unit/kg/hour (p = 0.10). Our findings suggest that aPTT monitoring may result in a delay to target attainment, higher UFH rates, and overall exposure.

INR Response to Low-Dose Vitamin K in Warfarin Patients.

BACKGROUND: Literature suggests that 2 mg of vitamin K intravenously (IV) provides a similar effect as 10 mg to reverse warfarin. Doses <5 mg haven't been studied in depth. OBJECTIVE: The objective was to determine the international normalized ratio (INR) reduction effect of ultra low-dose (ULD) IV vitamin K. METHODS: This retrospective, observational cohort study compared IV vitamin K doses of 0.25-0.5 mg (ULD) versus 1-2 mg (standard low dose [SLD]). The primary outcome assessed ΔINR at 36 hours; secondary outcomes assessed ΔINR at 12 hours and 30-day venous thromboembolism (VTE) and mortality rates. RESULTS: Of 88 patients identified (median baseline INR [IQR], 5.1 [3.1, 7.3] vs 4.5 [2.8, 8.2], ULD vs SLD, respectively), 59 had an INR at 12 hours. The ULD had fewer 12-hour INR values <2, with no statistical difference in the ΔINR at 12 hours between the ULD and SLD cohorts (median ΔINR, 2.2 [1.1, 3.4] vs 2.2 [1.1, 6.3]; P = 0.54; median INR, 2.3 vs 1.8). A total of 41 patients had both a 12- and 36-hour INR. No significant difference in the ΔINR between the 12- and 36-hour values occurred (median ΔINR, 0.52 [0.2, 0.91] vs ΔINR, 0.46 [0.18, 0.55]; P = 0.61), suggesting no rebound or excessive reversal and no difference in 30-day rates of VTE (P > 0.99) or death (P = 0.38). CONCLUSION AND RELEVANCE: ULD IV vitamin K reversed INR similarly to doses of 1-2 mg without rebound. A ULD strategy may be considered in patients requiring more cautious reversal.

Transitioning hospitalized patients from rivaroxaban or apixaban to a continuous unfractionated heparin infusion: A retrospective review.

PURPOSE: To determine a patient's clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin infusion. METHODS: A retrospective chart review was conducted to investigate how unfractionated heparin infusions were managed at a tertiary care hospital in the setting of recent apixaban or rivaroxaban administration. Patients were separated into 2 cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. The primary composite outcome was total number of bleeding and thrombotic events; the secondary composite outcome was average incidence of heparin infusion holds and rate changes per patient. RESULTS: Data were collected from 76 patients (heparin anti-Xa = 69, aPTT = 7). Due to the limited number of patients within the aPTT cohort, this data was excluded from the analysis, and heparin anti-Xa descriptive statistics were reported without statistical comparisons. In the heparin anti-Xa group, a total of 10 bleeds and 1 thrombus were discovered. Additionally, the average number of infusion holds and rate changes was 0.841 and 2.65 times per patient, respectively, for those patients monitored via heparin anti-Xa assay. CONCLUSION: In the presence of a recently administered oral anti-Xa anticoagulant, more down-titrations occurred in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, and most up-titrations occurred after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy.

Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum.

Coronavirus disease 2019 (COVID-19) is a viral infection that can, in severe cases, result in cytokine storm, systemic inflammatory response and coagulopathy that is prognostic of poor outcomes. While some, but not all, laboratory findings appear similar to sepsis-associated disseminated intravascular coagulopathy (DIC), COVID-19- induced coagulopathy (CIC) appears to be more prothrombotic than hemorrhagic. It has been postulated that CIC may be an uncontrolled immunothrombotic response to COVID-19, and there is growing evidence of venous and arterial thromboembolic events in these critically ill patients. Clinicians around the globe are challenged with rapidly identifying reasonable diagnostic, monitoring and anticoagulant strategies to safely and effectively manage these patients. Thoughtful use of proven, evidence-based approaches must be carefully balanced with integration of rapidly emerging evidence and growing experience. The goal of this document is to provide guidance from the Anticoagulation Forum, a North American organization of anticoagulation providers, regarding use of anticoagulant therapies in patients with COVID-19. We discuss in-hospital and post-discharge venous thromboembolism (VTE) prevention, treatment of suspected but unconfirmed VTE, laboratory monitoring of COVID-19, associated anticoagulant therapies, and essential elements for optimized transitions of care specific to patients with COVID-19.

Antibiotic Dosing for Critically Ill Adult Patients Receiving Intermittent Hemodialysis, Prolonged Intermittent Renal Replacement Therapy, and Continuous Renal Replacement Therapy: An Update.

Objective: To summarize current antibiotic dosing recommendations in critically ill patients receiving intermittent hemodialysis (IHD), prolonged intermittent renal replacement therapy (PIRRT), and continuous renal replacement therapy (CRRT), including considerations for individualizing therapy. Data Sources: A literature search of PubMed from January 2008 to May 2019 was performed to identify English-language literature in which dosing recommendations were proposed for antibiotics commonly used in critically ill patients receiving IHD, PIRRT, or CRRT. Study Selection and Data Extraction: All pertinent reviews, selected studies, and references were evaluated to ensure appropriateness for inclusion. Data Synthesis: Updated empirical dosing considerations are proposed for antibiotics in critically ill patients receiving IHD, PIRRT, and CRRT with recommendations for individualizing therapy. Relevance to Patient Care and Clinical Practice: This review defines principles for assessing renal function, identifies RRT system properties affecting drug clearance and drug properties affecting clearance during RRT, outlines pharmacokinetic and pharmacodynamic dosing considerations, reviews pertinent updates in the literature, develops updated empirical dosing recommendations, and highlights important factors for individualizing therapy in critically ill patients. Conclusions: Appropriate antimicrobial selection and dosing are vital to improve clinical outcomes. Dosing recommendations should be applied cautiously with efforts to consider local epidemiology and resistance patterns, antibiotic dosing and infusion strategies, renal replacement modalities, patient-specific considerations, severity of illness, residual renal function, comorbidities, and patient response to therapy. Recommendations provided herein are intended to serve as a guide in developing and revising therapy plans individualized to meet a patient's needs.

Bivalirudin Dosing Requirements in Adult Patients on Extracorporeal Life Support With or Without Continuous Renal Replacement Therapy.

Systemic anticoagulation with unfractionated heparin is standard of care for patients receiving extracorporeal life support (ECLS); however, an alternative anticoagulant may be necessary when challenges with heparin therapy arise. Evidence for alternative anticoagulation in ECLS patients is limited. This retrospective analysis evaluated the dosing and outcomes associated with bivalirudin use in 14 adult ECLS patients. Indications for bivalirudin included heparin-induced thrombocytopenia, heparin resistance, or persistent clotting or bleeding while on heparin. The median initial bivalirudin dose to achieve target activated partial thromboplastin time was 0.15 mg/kg/h (range 0.04-0.26 mg/kg/h). Dosing requirements increased by 75-125% when renal replacement was included. Median time on bivalirudin was 5.2 days (range 0.9-28 days). Five patients (36%) required a circuit change while on bivalirudin because of clotting or failing oxygenation, and four (28.6%) had bleeding significant enough to require either reduction in activated partial thromboplastin time goals or temporary holding of anticoagulation. Bivalirudin appears to be a potential option for adult patients on ECLS who are unable to receive or fail heparin therapy; however, the wide variation in dosing suggests the need for careful management.

Incomplete dabigatran reversal with idarucizumab.

CONTEXT: With increasing use of direct oral anticoagulants (DOACs), urgent reversal of these agents becomes a growing concern. Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with higher affinity than thrombin, rapidly neutralizing its anticoagulant effect without increased risk of thrombosis. CASE DETAILS: We describe two cases in which the recommended dose of idarucizumab was unsuccessful in completely reversing the anticoagulant effects of dabigatran. Both of these patients were noted to have supratherapeutic international normalized ratios (INRs) and high dabigatran concentrations. In the first case, an 86-year-old male underwent an emergent procedure and experienced excessive hemorrhaging refractory to blood product repletion, idarucizumab, and factor eight inhibitor bypass activity (FEIBA). In the second case, a 62-year-old female in shock was found to have elevated dabigatran concentrations despite two doses of idarucizumab, continuous renal replacement therapy (CRRT), blood product repletion, and FEIBA. Both patients ultimately expired from their coagulopathies. DISCUSSION: These cases illustrate the potential for incomplete reversal of dabigatran with the recommended 5 g of idarucizumab and emphasize the importance of early detection of dabigatran toxicity. While direct dabigatran serum concentrations are not readily available, the INR may be a useful surrogate marker for supratherapeutic dabigatran concentrations.