Faculty Bibliography

The oral factor Xa inhibitors (OFXAi) apixaban and rivaroxaban are increasingly utilized for the treatment of venous thromboembolism (VTE) with recommended initial higher dose 7- and 21-day lead-in regimens, respectively. In patients receiving initial parenteral anticoagulation, it remains unknown if the full recommended higher dose OFXAi lead-in regimens are warranted, or if days can be subtracted. We aimed to describe when clinicians may deviate from recommended lead-in durations and evaluate clinical outcomes in these scenarios. This is a retrospective, observational study of patients 18 years or older who were treated with rivaroxaban or apixaban for acute pulmonary embolism (PE) or symptomatic proximal deep vein thrombosis (DVT) that received parenteral anticoagulation for at least 24 h before transitioning to the OFXAi. Among our cohort of 171 patients with acute VTE who received parenteral anticoagulation for a median of 48 h, 134 (78%) were prescribed a full OFXAi lead-in and 37 (22%) were prescribed a reduced lead-in. Patients in the reduced lead-in group were older with more cardiac comorbidities and antiplatelet use. There were four recurrent thromboembolic events within 3 months, two in the reduced lead-in group and two in the full lead-in group (5% vs. 2%, p = 0.206). Bleeding within 3 months occurred in 9 (5%) patients, with 6 events occurring in the reduced lead-in group and 3 events in the full lead-in group (16% vs. 2%, p = 0.004). Prescribing patterns of OFXAi lead-in therapy duration are variable in patients receiving initial parenteral anticoagulation. Larger cohorts are needed to better define the safety and efficacy of lead-in reduction.

Nucleoside or nucleotide analogues (NAs) have the potential to cause lactic acidosis by inhibiting DNA polymerase-γ of human mitochondria and impairing aerobic metabolism. Patients may be asymptomatic, have mild non-specific symptoms, or present in multisystem organ failure. There is a paucity of data to guide management of life-threatening lactic acidosis due to NA therapy. Here we describe a case of a 60-year old critically ill male with decompensated cirrhosis secondary to hepatitis B virus (HBV) infection who developed severe lactic acidosis (13.8 mmol/L) 2 days after initiation of tenofovir alafenamide (TAF). All other possible etiologies for the elevated lactate were ruled out. Lactic acidosis resolved rapidly with TAF discontinuation and supplementation with cofactors supporting mitochondrial oxidative phosphorylation, including coenzyme Q10, levocarnitine, riboflavin, and thiamine. This case highlights the ability of TAF to cause lactic acidosis early after therapy initiation, especially in susceptible hosts, and reviews the potential role for cofactor supplementation for drug-induced mitochondrial injury.

BACKGROUND/UNASSIGNED:Corticosteroids and tocilizumab have been shown to improve survival in patients who require supplemental oxygen from coronavirus disease 2019 (COVID-19) pneumonia. The optimal dose of immunosuppression for the treatment of COVID-19 acute respiratory distress syndrome (ARDS) is still unknown. OBJECTIVE/UNASSIGNED:The objective of this study was to evaluate the effectiveness and safety of high- versus low-dose corticosteroids with or without tocilizumab for the treatment of COVID-19 ARDS. METHODS/UNASSIGNED:This was a retrospective study of patients admitted to the intensive care unit (ICU) requiring mechanical ventilation who received high- versus low-dose corticosteroids with or without tocilizumab. The primary outcome was survival to discharge. Safety outcomes included infections and incidence of hyperglycemia. RESULTS/UNASSIGNED:= 0.01). The highest rate of a bacterial pneumonia was in patients who received high-dose corticosteroids with tocilizumab. CONCLUSIONS/UNASSIGNED:In critically ill patients with COVID-19 ARDS requiring mechanical ventilation, we found no difference in high- versus low-dose corticosteroids with regard to survival to hospital discharge. However, patients receiving only low-dose corticosteroids without tocilizumab did worse than the other groups. Larger prospective studies are needed to determine the optimal immunosuppression dosing strategy in this patient population.

The use of acute mechanical circulatory support (MCS) has increased over the last decade. For patients with left-ventricular failure, an Impella^® (Abiomed, Danvers, MA) may be used to improve cardiac output. The purpose of this study is to describe Impella^® anticoagulation patterns and evaluate the safety and effectiveness of our protocol. This is a retrospective review of all adult patients who required at least 24 h of Impella^® support and received a heparin-based purge solution. In total, 109 patients were included in the final analysis. The most common indication for Impella^® device insertion was cardiogenic shock (76%) with the remaining patients receiving a device for a high-risk procedures; typically coronary artery bypass grafting or percutaneous coronary intervention. A total of 9 thrombotic events occurred among 8 (7%) patients and 50 bleeding events occurred among 43 (39%) patients, with the most common classification being BARC 3a (60%). A univariate analysis revealed that patients were more likely to bleed if they were less than 65 years old, had an indication of cardiogenic shock for Impella^®, inserted the device peripherally, were on dual antiplatelet therapy, or had an intra-aortic balloon pump prior to Impella^® insertion, the latter of which was confirmed with a multivariate analysis (OR 2.5 [1.072-5.830]; p = 0.034). For those monitored by anti-Xa, the presence of two or more values greater than 0.40 IU/mL was a risk factor for bleeding (p = 0.037). Our study identifies risk factors for bleeding in patients receiving temporary MCS with an Impella^®.

The backbone induction therapy for primary central nervous system lymphoma (PCNSL) is high dose methotrexate (HD-MTX) and rituximab, which can be combined with other chemotherapeutic agents. The optimal dose of HD-MTX remains unclear, as doses between 3 and 8 g/m² have been shown to be effective. In this retrospective study, HD-MTX dosed at 3-5 g/m² demonstrated an overall response of 81.8%, with 11 (50%) complete responses. The median overall survival was not met at 29 months and median progression free survival was 12.5 months.There were two discontinuations due to nephrotoxicity. The most common adverse event was hepatotoxicity (18.5%), with no treatment-related mortality events observed.Overall, HD-MTX dosed at 3-5 g/m² demonstrated similar efficacy and lower toxicity compared to higher doses in PCNSL patients. Reducing the initial HD-MTX dose may help ensure tolerability and completion of induction therapy, especially in patients with co-morbidities or older age who have poorer outcomes.

Background/UNASSIGNED:Limited data support use of pneumococcal urinary antigen testing (PUAT) for patients with community-acquired pneumonia (CAP) as an antimicrobial stewardship tool. At our institution, CAP guidelines and admission order set were standardized to include universal PUAT. Methods/UNASSIGNED:This was a retrospective study of adults hospitalized in 2019 who had PUAT performed. We compared incidence and timing of de-escalation in PUAT- positive vs -negative groups and described patients' outcomes. Results/UNASSIGNED:, in-hospital mortality, or 30-day infection-related readmission. Conclusions/UNASSIGNED:We observed earlier de-escalation in the PUAT-positive group. This seems to be due to discontinuation of atypical rather than anti-MRSA or antipseudomonal coverage. Further antimicrobial stewardship interventions are warranted.

Cardiac arrest has many implications for morbidity and mortality. Few interventions have been shown to improve return of spontaneous circulation (ROSC) and long-term outcomes after cardiac arrest. Ischemic-reperfusion injury upon achieving ROSC creates an imbalance between oxygen supply and demand. Multiple events occur in the postcardiac arrest period, including excitotoxicity, mitochondrial dysfunction, and oxidative stress and inflammation, all of which contribute to ongoing brain injury and cellular death. Given that complex pathophysiology underlies global brain hypoxic ischemia, neuroprotective strategies targeting multiple stages of the neuropathologic cascade should be considered as a means of mitigating secondary neuronal injury and improving neurologic outcomes and survival in cardiac arrest victims. In this review article, we discuss a number of different pharmacologic agents that may have a potential role in targeting these injurious pathways following cardiac arrest. Pharmacologic therapies most relevant for discussion currently include memantine, perampanel, magnesium, propofol, thiamine, methylene blue, vitamin C, vitamin E, coenzyme Q₁₀ , minocycline, steroids, and aspirin.

INTRODUCTION: Vasodilatory shock may arise after cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) and can require salvage therapy with either hydroxocobalamin (HCB) or methylene blue (MB). Data is limited regarding the optimal agent and dosing strategy for each situation.
METHOD(S): This is a retrospective review of patients who received HCB or MB at NYU Langone Health for refractory vasodilatory shock that occurred within 48 hr after CPB or ECMO cannulation. The primary endpoint was the change in vasopressor requirement at 6, 12, 24, and 48 hr after intervention, characterized as both norepinephrine equivalents (NEE) and vasoactive inotropic score (VIS).
RESULT(S): Thirty patients were identified, of which 15 received HCB and 15 received MB. Patients were primarily male (70%) with a median age of 67 and SOFA score of 10. Indications for salvage therapy included postcardiotomy shock (70%) and ECMO cannulation (30%). Dosing strategies included bolus only (9 HCB; 6 MB) or bolus plus infusion (6 HCB; 9 MB), with infusions continuing for a median of 6 hr (5, 6) for HCB and 11 hr (6, 24) for MB. The median cumulative dose was 5000 mg (5000, 10000) for HCB and 5 mg/kg (1.75, 6.8) for MB. Baseline NEE prior to drug administration was 0.42 mcg/kg/min for HCB vs 0.5 mcg/kg/min for MB (p=0.98), and baseline VIS was 28 for HCB vs 23 for MB (p=0.44). Patients who received HCB had a greater percentage change in NEE compared to MB at 6 hr (-72% [-84, -40] vs 0% [-16, +29], p< 0.01) and 12 hr (-73% [-88, -55] vs -39% [-59, +8]; p< 0.01), as well as VIS at 6 hr (-42% [-56, -30] vs 0% [-10, +32]; p< 0.01) and 12 hr (-50% [-78, -32] vs -15% [-41, +17]; p< 0.01). No differences in NEE or VIS were observed at 24 or 48 hr. The bolus plus infusion dosing strategy led to a faster resolution of shock than bolus alone for HCB (27 hr [20, 37] vs 140 hr [98, 436]; p< 0.01) but not for MB (136 hr [30, 251] vs 233 hr [206, 260]; p=0.55). There were no differences in adverse drug events between groups.
CONCLUSION(S): We observed greater differences in change in NEE and VIS favoring the use of HCB over MB at 6 and 12 hr, but not at 24 or 48 hr. A HCB dosing strategy of bolus followed by infusion demonstrated a faster resolution of shock in comparison to bolus alone. Further research is required to confirm these results

Prescribing patterns for oral anticoagulants in patients with nonvalvular atrial fibrillation and venous thromboembolism is shifting from vitamin K antagonists, such as warfarin to the direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, and apixaban. Although many hospital systems have implemented clinical decision support or enhanced monitoring for patients prescribed warfarin, there is limited evidence to suggest similar levels of enhanced monitoring for DOACs. The antithrombotic stewardship team at our institution developed guidelines and implemented computerized clinical decision support (CCDS) tools to enhance medication and patient safety related to the DOACs. We sought to assess the safety and effectiveness of these CCDS tools available to clinicians upon DOAC prescription in hospitalized patients. We performed a retrospective review of 121 patients who received at least two doses of a DOAC from January 2013 to July 2014. We assessed dosing of the DOAC according to the CCDS provided upon order entry. Adherence to CCDS was 80% (n = 24), 75% (n = 46), and 87% (n = 27) in the dabigatran, apixaban, and rivaroxaban group, respectively. Our data demonstrate that implementing CCDS for DOACs into the electronic medical record may ensure safe prescribing of high-risk medications.

Objective/UNASSIGNED:Drug interactions are a common cause of morbidity and mortality and may require prompt discontinuation of therapeutic regimens due to harmful side effects. Patients with acute coronary syndromes are likely to be prescribed multiple medications that are metabolized through the cytochrome P450 system, increasing the probability for drug interaction. Atorvastatin and simvastatin are both well known to interact with the oral P2Y12 agent ticagrelor. The purpose of this paper is to describe the interaction of ticagrelor with rosuvastatin leading to rhabdomyolysis, which is less clearly defined in the literature. Method/UNASSIGNED:We report a case of a 74-year-old male who presented with bilateral lower extremity weakness and difficulty ambulating for one month after being prescribed ticagrelor for a drug eluting stent, in the setting of already being on rosuvastatin. His clinical picture and laboratory findings were consistent with a diagnosis of rhabdomyolysis. His medications were adjusted to a regimen of clopidogrel and alirocumab. One month later, he returned to his baseline status. Results/UNASSIGNED:The mechanism of interaction between rosuvastatin and ticagrelor appears to be multifactorial. It may be caused by CYP450-mediated metabolism from a small amount of crossover between isoenzymes. Ticagrelor may also cause acute kidney injury, increasing the concentration of rosuvastatin. Other mechanisms of interaction include genetic differences in the organic anion transporter polypeptides and transportation through p-glycoprotein. Conclusion/UNASSIGNED:Future pharmacokinetic studies are warranted to better understand the interaction.