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.

Virtual Care Team Guided Management of Patients With Heart Failure During Hospitalization.

BACKGROUND: Scalable and safe approaches for heart failure guideline-directed medical therapy (GDMT) optimization are needed. OBJECTIVES: The authors assessed the safety and effectiveness of a virtual care team guided strategy on GDMT optimization in hospitalized patients with heart failure with reduced ejection fraction (HFrEF). METHODS: In a multicenter implementation trial, we allocated 252 hospital encounters in patients with left ventricular ejection fraction ≤40% to a virtual care team guided strategy (107 encounters among 83 patients) or usual care (145 encounters among 115 patients) across 3 centers in an integrated health system. In the virtual care team group, clinicians received up to 1 daily GDMT optimization suggestion from a physician-pharmacist team. The primary effectiveness outcome was in-hospital change in GDMT optimization score (+2 initiations, +1 dose up-titrations, -1 dose down-titrations, -2 discontinuations summed across classes). In-hospital safety outcomes were adjudicated by an independent clinical events committee. RESULTS: Among 252 encounters, the mean age was 69 ± 14 years, 85 (34%) were women, 35 (14%) were Black, and 43 (17%) were Hispanic. The virtual care team strategy significantly improved GDMT optimization scores vs usual care (adjusted difference: +1.2; 95% CI: 0.7-1.8; P < 0.001). New initiations (44% vs 23%; absolute difference: +21%; P = 0.001) and net intensifications (44% vs 24%; absolute difference: +20%; P = 0.002) during hospitalization were higher in the virtual care team group, translating to a number needed to intervene of 5 encounters. Overall, 23 (21%) in the virtual care team group and 40 (28%) in usual care experienced 1 or more adverse events (P = 0.30). Acute kidney injury, bradycardia, hypotension, hyperkalemia, and hospital length of stay were similar between groups. CONCLUSIONS: Among patients hospitalized with HFrEF, a virtual care team guided strategy for GDMT optimization was safe and improved GDMT across multiple hospitals in an integrated health system. Virtual teams represent a centralized and scalable approach to optimize GDMT.

Contemporary Trends in the Use of and Expenditures on Digoxin in the United States.

BACKGROUND: Digoxin is indicated for the management of heart failure with reduced ejection fraction and atrial fibrillation. Despite stronger guideline recommendations for other pharmacologic and device therapies, digoxin retains a role in select patients unable to tolerate or refractory to standard therapies. Contemporary utilization of and costs related to digoxin in the United States of America (USA) remain uncharacterized. The objective of this study was to estimate trends in digoxin use and expenditures across the USA from 2010 to 2017. METHODS: We utilized the Medical Expenditure Panel Survey to estimate trends in digoxin use and expenditures across the USA from 2010 to 2017. The Medical Expenditure Panel Survey is an overlapping panel survey that interviews households in the USA to ascertain their healthcare utilization and expenditures. Complex sampling procedures allow for nationally representative estimates of utilization and expenditures. We report the number of digoxin users and expenditures across key subgroups in 2-year increments from 2010 to 2017. RESULTS: The number of digoxin users in the USA declined by 47% from 766 users per 100,000 adults in 2010-11 to 402 users per 100,000 adults in 2016-17. While digoxin use declined among women and self-identified White adults, adults living at or below the federal poverty level and those who self-identified as Asian or Hispanic represent an increasing proportion of overall digoxin users. While nationwide digoxin expenditures declined by 26% from 2010-11 to 2012-13, they peaked at $260.3 million in 2014-15 and remained elevated at $188.7 million in 2016-17. CONCLUSIONS: Despite a nationwide trend towards declining use, digoxin remains prevalent amongst people of Asian and Hispanic descent in the USA. After a spike in cost in 2013, digoxin prices have yet to return to pre-spike levels. The role of digoxin in contemporary heart failure and arrhythmia management will continue to evolve as additional randomized and observational analyses become available.

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.

Patient-provider discussions of bariatric surgery and subsequent weight changes and receipt of bariatric surgery.

OBJECTIVE: The purpose of this study was to determine whether patients who discuss bariatric surgery with their providers are more likely to undergo the procedure and to lose weight. METHODS: A retrospective cohort study of adults with BMI ≥ 35 kg/m2 treated between 2000 and 2015 was conducted to analyze the relationship between a discussion of bariatric surgery in the first year after study entry and weight changes (primary outcome) and receipt of bariatric surgery (secondary outcome) over 2 years after study entry. Natural language processing was used to identify the documentation of bariatric surgery discussion in electronic provider notes. RESULTS: Out of 30,560 study patients, a total of 2,659 (8.7%) discussed bariatric surgery with their providers. The BMI of patients who discussed bariatric surgery decreased by 2.18 versus 0.21 for patients who did not (p < 0.001). In a multivariable analysis, patients who discussed bariatric surgery with their providers lost more weight (by 1.43 [change in BMI]; 95% CI: 1.29-1.57) and had greater odds (10.2; 95% CI: 9.0-11.6; p < 0.001) of undergoing bariatric surgery. CONCLUSIONS: Clinicians rarely discussed bariatric surgery with their patients. Patients who did have this discussion were more likely to lose weight and to undergo bariatric surgery.

Virtual optimization of guideline-directed medical therapy in hospitalized patients with heart failure with reduced ejection fraction: the IMPLEMENT-HF pilot study.

AIMS: Implementation of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains incomplete. Non-cardiovascular hospitalization may present opportunities for GDMT optimization. We assessed the efficacy and durability of a virtual, multidisciplinary 'GDMT Team' on medical therapy prescription for HFrEF. METHODS AND RESULTS: Consecutive hospitalizations in patients with HFrEF (ejection fraction ≤40%) were prospectively identified from 3 February to 1 March 2020 (usual care group) and 2 March to 28 August 2020 (intervention group). Patients with critical illness, de novo heart failure, and systolic blood pressure <90 mmHg in the preceeding 24 hs prior to enrollment were excluded. In the intervention group, a pharmacist-physician GDMT Team provided optimization suggestions to treating teams based on an evidence-based algorithm. The primary outcome was a GDMT optimization score, the sum of positive (+1 for new initiations or up-titrations) and negative therapeutic changes (-1 for discontinuations or down-titrations) at hospital discharge. Serious in-hospital safety events were assessed. Among 278 consecutive encounters with HFrEF, 118 met eligibility criteria; 29 (25%) received usual care and 89 (75%) received the GDMT Team intervention. Among usual care encounters, there were no changes in GDMT prescription during hospitalization. In the intervention group, ß-blocker (72% to 88%; P = 0.01), angiotensin receptor-neprilysin inhibitor (6% to 17%; P = 0.03), mineralocorticoid receptor antagonist (16% to 29%; P = 0.05), and triple therapy (9% to 26%; P < 0.01) prescriptions increased during hospitalization. After adjustment for clinically relevant covariates, the GDMT Team was associated with an increase in GDMT optimization score (+0.58; 95% confidence interval +0.09 to +1.07; P = 0.02). There were no serious in-hospital adverse events. CONCLUSIONS: Non-cardiovascular hospitalizations are a potentially safe and effective setting for GDMT optimization. A virtual GDMT Team was associated with improved heart failure therapeutic optimization. This implementation strategy warrants testing in a prospective randomized controlled trial.

Evaluation of Direct Oral Anticoagulant Prescribing in Patients With Moderate to Severe Renal Impairment.

Patients with renal impairment require dose adjustments for direct oral anticoagulants (DOACs), though there is uncertainty regarding their use in severe chronic kidney disease. Inappropriately dosed DOACs may increase risk of ischemic events when under-dosed, or risk of bleeding when over-dosed. The purpose of this study was to describe DOAC selection, dosing strategies, and associated clinical outcomes in patients with moderate to severe renal impairment at our institution. This was a single-center retrospective analysis of adult outpatients with moderate to severe renal impairment (estimated creatinine clearance <50 mL/min, including need for hemodialysis) who were prescribed a DOAC by a cardiologist between June 1, 2015 and December 1, 2018. Outcomes evaluated included the percentage of patients who received appropriate and inappropriate DOAC dosing, prescriber reasons for inappropriate DOAC dosing if documented, and incidence of thrombotic and bleeding events. A total of 207 patients were included. Overall, 61 (29.5%) patients received inappropriate dosing, with 43 (70.5%) being under-dosed and 18 (29.5%) being over-dosed as compared to FDA-labeled dosing recommendations for atrial fibrillation or venous thromboembolism (VTE). By a median follow-up duration of 20 months, stroke occurred in 6 (3.3%) patients receiving DOACs for atrial fibrillation, and VTE occurred in 1 (4.3%) patient receiving a DOAC for VTE. International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding occurred in 25 (12.1%) patients. Direct oral anticoagulants were frequently prescribed at off-label doses in patients with moderate to severe renal impairment, with a tendency toward under-dosing.

Safety of Intravenous Push Lacosamide Compared With Intravenous Piggyback at a Tertiary Academic Medical Center.

BACKGROUND: There are limited data regarding the incidence of adverse events associated with administering lacosamide by intravenous push (IVP) compared with IV piggyback (IVPB). OBJECTIVE: The objective of this analysis was to compare the safety profile, including cardiovascular effects, sedative effects, and IV site reactions of IVP and IVPB lacosamide administration. METHODS: A retrospective pre/post cohort analysis comparing patients who received lacosamide via IVP and IVPB was conducted. Safety end points included hypotension, bradycardia, medication-related sedation, and IV site reactions. The relationship between patient characteristics and the incidence of safety end points was analyzed using the Student t-test and χ2 test as appropriate. RESULTS: Bradycardia occurred after 0.19% of IVP administrations and 1.09% of IVPB administrations assessed (P = 0.07). Hypotension was observed in 3.16% of IVP administrations compared to 1.59% in the IVPB cohort (P = 0.12). Post lacosamide-related sedation was noted in 11.32% and 11.68% of the IVP and IVPB cohorts, respectively (P = 0.87). Infusion site reaction rates of 1.80% and 0.84% were documented in the IVP and IVPB cohorts, respectively (P = 0.33). Of note, only 1 adverse event required clinical intervention. One 200-mg dose in the IVP cohort required a fluid bolus postadministration. CONCLUSION AND RELEVANCE: IVP lacosamide was associated with a similar incidence of cardiovascular, neurological, and infusion site-related adverse events compared with IVPB, in which nearly every adverse event was deemed clinically insignificant. Lacosamide administered via IVP may be considered a safe alternative method of administration in the acute care setting.

Role for Anti-Cytokine Therapies in Severe Coronavirus Disease 2019.

The causative agent for coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, appears exceptional in its virulence and immunopathology. In some patients, the resulting hyperinflammation resembles a cytokine release syndrome. Our knowledge of the immunopathogenesis of coronavirus disease 2019 is evolving and anti-cytokine therapies are under active investigation. This narrative review summarizes existing knowledge of the immune response to coronavirus infection and highlights the current and potential future roles of therapeutic strategies to combat the hyperinflammatory response of patients with coronavirus disease 2019. DATA SOURCES: Relevant and up-to-date literature, media reports, and author experiences were included from Medline, national newspapers, and public clinical trial databases. STUDY SELECTION: The authors selected studies for inclusion by consensus. DATA EXTRACTION: The authors reviewed each study and selected approrpriate data for inclusion through consensus. DATA SYNTHESIS: Hyperinflammation, reminiscent of cytokine release syndromes such as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, appears to drive outcomes among adults with severe coronavirus disease 2019. Cytokines, particularly interleukin-1 and interleukin-6, appear to contribute importantly to such systemic hyperinflammation. Ongoing clinical trials will determine the efficacy and safety of anti-cytokine therapies in coronavirus disease 2019. In the interim, anti-cytokine therapies may provide a treatment option for adults with severe coronavirus disease 2019 unresponsive to standard critical care management, including ventilation. CONCLUSIONS: This review provides an overview of the current understanding of the immunopathogenesis of coronavirus disease 2019 in adults and proposes treatment considerations for anti-cytokine therapy use in adults with severe disease.

Changes in nationwide Medicare and Medicaid expenditures on lipid-lowering therapies after proprotein convertase/subtilisin type 9 inhibitor availability.

BACKGROUND: Several advances in lipid-lowering pharmacotherapy and changes in generic formulation availability occurred between 2013 and 2017. OBJECTIVE: We sought to examine nationwide trends in Medicare Part D and Medicaid expenditures on lipid-lowering therapies from 2013 to 2017. METHODS: We aggregated 662.2 million Medicare Part D and Medicaid prescription claims with associated expense data for 2013 to 2017 from the Medicare and Medicaid Drug Spending Dashboards for nine therapeutic classes of lipid-lowering therapies. RESULTS: Total Medicare Part D expenditures on lipid-lowering therapies was $7.01 billion in 2013 and $5.07 billion in 2017. Total Medicaid lipid-lowering therapy expenditures decreased from $440.9 million in 2013 to $398.7 million in 2017. Annual Medicare expenditures on Crestor were $2.2 billion in 2013 and $0.31 billion in 2017. Annual Medicaid Crestor expenditures decreased from $92.4 million in 2013 to $30.1 million in 2017. From 2013 to 2016, Medicare expenditures on Zetia decreased from $0.89 billion to $0.70 billion, whereas Medicaid Zetia expenditures decreased from $38.6 million in 2013 to $25.4 million in 2017. In 2017, PCSK9 inhibitors accounted for $317.3 million and $14.2 million in Medicare and Medicaid expenditures, respectively. CONCLUSIONS: Overall Medicare and Medicaid expenditures on lipid-lowering therapies decreased by $2.5 billion from 2013 to 2017.

Assessment of Sotalol and Dofetilide Dosing at a Large Academic Medical Center.

BACKGROUND: Patients initiated on sotalol and dofetilide require inpatient monitoring and dose adjustments due to risks of corrected QT (QTc) prolongation and Torsades de pointes (TdP). Patients may receive higher initial doses than recommended due to close monitoring by specialized practitioners. The objective of this study was to describe prescribing practices of sotalol and dofetilide and to compare safety outcomes between standard and nonstandard dosing strategies. METHODS: This was a single-center retrospective analysis of adult inpatients who underwent sotalol or dofetilide initiation between June 1, 2015, and August 1, 2018. The end points of this study included the percentage of patients who received standard and nonstandard dosing, incidence of QTc prolongation (≥500 milliseconds or ≥15% from baseline), incidence of TdP, and dose reduction or medication discontinuation. RESULTS: A total of 379 patients (195 sotalol and 184 dofetilide) were included in this analysis. There were 110 (56.4%) patients in the sotalol group and 111 (58.4%) patients in the dofetilide group that received nonstandard initial dosing. Nonstandard dosing was associated with a greater incidence of QTc prolongation compared to standard dosing (57.5% vs 43.0%, P = .005). Only one patient in the nonstandard dosing group experienced TdP. Patients initiated on nonstandard dosing required dose reduction or therapy discontinuation (37.6% vs 23.4%, P = .003) more frequently. CONCLUSION: Higher than recommended initial doses of sotalol or dofetilide were associated with higher incidence of QTc prolongation and more frequent therapy modification.

Time in the Therapeutic Range for Assessing Anticoagulation Quality in Patients Receiving Continuous Unfractionated Heparin.

Due to variable pharmacokinetic properties, therapeutic anticoagulation with continuous unfractionated heparin (UFH) requires ongoing laboratory monitoring, generally with activated partial thromboplastin time (aPTT). In the ambulatory setting, clinicians who manage warfarin therapy often use time in the therapeutic range (TTR) to estimate a percentage of time the international normalized ratio is therapeutic. We applied the TTR concept to aPTT monitoring for therapeutic UFH and used 2 methodologies for estimation: percentage of aPTT values in range (%aIR) and a modification of the Rosendaal method (mod-Rosendaal). This study included adult inpatients admitted between September 30, 2015, and September 30, 2016, at Brigham and Women's Hospital. For each patient, all available aPTT values were extracted to calculate 2 individual TTRs according to each methodology. Comparison between methods was performed using Student t test, and correlation was assessed with simple linear regression. A total of 255 patients were included in this study. The major outcome of TTR estimation was significantly higher using mod-Rosendaal (43.7% [26.5%]) versus %aIR (37.7% [25.7%], P = .012) by a mean difference of 6% points (95% confidence interval: 1.3-10.7). Time in the therapeutic range estimated by mod-Rosendaal significantly correlated with those estimated by %aIR (r = 0.84, P < .001). Further studies should evaluate the correlation between TTR and clinical outcomes and establish a benchmark for quality therapeutic anticoagulation with continuous UFH.

Expanding anticoagulation management services to include direct oral anticoagulants.

Despite the ease of use of direct oral anticoagulants (DOACs), these agents remain high risk medications and their clinical efficacy can be impacted by factors such as patient adherence, drug procurement barriers, bleeding leading to discontinuation, and prescribing that deviates from approved dosing regimens. Clinical monitoring of patients on DOACs should be performed by clinicians who specialize in anticoagulation and are familiar with the nuances of DOAC dosing, monitoring, and other components of anticoagulation management including peri-procedural management and care transitions. Although data for centralized warfarin management have consistently demonstrated improved clinical outcomes compared to traditional management by individual community providers, there are no published data addressing the impact of centralized management of DOACs on clinical outcomes or anticoagulation control. In addition, there is currently no consensus on how to incorporate patients on DOACs into this centralized model, despite recommendations for systematic follow-up by both the Anticoagulation Forum and the Institute for Safe Medication Practices. Based on the national recommendations and an identified institutional need, the Brigham and Women's Hospital Anticoagulation Management Service implemented a pilot program to expand services to include patients newly initiated on, or transitioned to, a DOAC. We describe our model for expansion of the AMS to include patients on DOACs.