Anti-factor Xa as the preferred assay to monitor heparin for the treatment of pulmonary embolism.

INTRODUCTION: The mainstay of acute pulmonary embolism (PE) treatment is anticoagulation. Timely anticoagulation correlates with decreased PE-associated mortality, but the ability to achieve a therapeutic activated partial thromboplastin time (aPTT) with unfractionated heparin (UFH) remains limited. Although some institutions have switched to a more accurate and reproducible test to assess for heparin's effectiveness, the anti-factor Xa (antiXa) assay, data correlating a timely therapeutic antiXa to PE-associated clinical outcomes remains scarce. We evaluated time to a therapeutic antiXa using intravenous heparin after PE response team (PERT) activation and assessed clinical outcomes including bleeding and recurrent thromboembolic events. METHODS: This was a retrospective cohort study at NYU Langone Health. All adult patients ≥18 years with a confirmed PE started on IV UFH with >2 antiXa levels were included. Patients were excluded if they received thrombolysis or alternative anticoagulation. The primary endpoint was the time to a therapeutic antiXa level of 0.3-0.7 units/mL. Secondary outcomes included recurrent thromboembolism, bleeding and PE-associated mortality within 3 months. RESULTS: A total of 330 patients with a PERT consult were identified with 192 patients included. The majority of PEs were classified as sub massive (64.6%) with 87% of patients receiving a bolus of 80 units/kg of UFH prior to starting an infusion at 18 units/kg/hour. The median time to the first therapeutic antiXa was 9.13 hours with 93% of the cohort sustaining therapeutic anticoagulation at 48 hours. Recurrent thromboembolism, bleeding and mortality occurred in 1%, 5% and 6.2%, respectively. Upon univariate analysis, a first antiXa <0.3 units/ml was associated with an increased risk of mortality [27.78% (5/18) vs 8.05% (14/174), p = 0.021]. CONCLUSION: We observed a low incidence of recurrent thromboembolism or PE-associated mortality utilizing an antiXa titrated UFH protocol. The use of an antiXa based heparin assay to guide heparin dosing and monitoring allows for timely and sustained therapeutic anticoagulation for treatment of PE.

To Measure or Not to Measure: Direct Oral Anticoagulant Laboratory Assay Monitoring in Clinical Practice.

The need for therapeutic drug monitoring of direct oral anticoagulants (DOACs) remains an area of clinical equipoise. Although routine monitoring may be unnecessary given predictable pharmacokinetics in most patients, there may be altered pharmacokinetics in those with end organ dysfunction, such as those with renal impairment, or with concomitant interacting medications, at extremes of body weight or age, or in those with thromboembolic events in atypical locations. We aimed to assess real-world practices in situations in which DOAC drug-level monitoring was used at a large academic medical center. A retrospective review of the records of patients who had a DOAC drug-specific activity level checked from 2016 to 2019 was included. A total of 119 patients had 144 DOAC measurements (apixaban (n = 62) and rivaroxaban (n = 57)). Drug-specific calibrated DOAC levels were within an expected therapeutic range for 110 levels(76%), with 21 levels (15%) above the expected range and 13 levels (9%) below the expected range. The DOAC levels were checked in the setting of an urgent or emergent procedure in 28 patients (24%), followed by renal failure in 17 patients (14%), a bleeding event in 11 patients (9%), concern for recurrent thromboembolism in 10 patients (8%), thrombophilia in 9 patients (8%), a history of recurrent thromboembolism in 6 patients (5%), extremes of body weight in 7 patients (5%), and unknown reasons in 7 patients (5%). Clinical decision making was infrequently affected by the DOAC monitoring. Therapeutic drug monitoring with DOACs may help predict bleeding events in elderly patients, those with impaired renal function, and in the event of an emergent or urgent procedure. Future studies are needed to target the select patient-specific scenarios where monitoring DOAC levels may impact clinical outcomes.

Real world prescribing practices of apixaban or rivaroxaban lead-in doses for the treatment of venous thromboembolism in hospitalized patients.

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.

Antithrombotic Stewardship: Assessing Use of Computerized Clinical Decision Support Tools to Enhance Safe Prescribing of Direct Oral Anticoagulants in Hospitalized Patients.

ABSTRACT: 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.

Antithrombotic and hemostatic stewardship: evaluation of clinical outcomes and adverse events of recombinant factor VIIa (Novoseven®) utilization at a large academic medical center.

BACKGROUND: Recombinant factor VIIa (rFVIIa) (Novoseven®) is utilized for the reversal of anticoagulation-associated bleeding and refractory bleeding in cardiac surgery. In August 2015, rFVIIa was transferred from the blood bank to the pharmacy at New York University (NYU) Langone Health. Concordantly, an off-label dosing guideline was developed. The objective of this study was to describe utilization and cost of rFVIIa and assess compliance to our dosing guideline. METHODS: We performed a retrospective, observational review of rFVIIa administrations post-implementation of an off-label dosing guideline. All patients who received rFVIIa between September 2015 and June 2017 were evaluated. For each rFVIIa administration, anticoagulation and laboratory values, indications for use, dosing, ordering and administration times, concomitant blood products, and adverse events were collected. Adverse events included venous thromboembolism, stroke, myocardial infarction, and death due to systemic embolism and mortality. The primary endpoint was the utilization of rFVIIa in accordance with the off-label dosing guideline. Secondary endpoints included hemostatic efficacy of rFVIIa, adverse events, blood products administered, and cost-effectiveness of rFVIIa transition to pharmacy. RESULTS: A total of 63 patients [pediatric (n = 6), adult (n = 57)] received rFVIIa, with the majority of use for refractory bleeding after cardiac surgery. The utilization of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous; 70% of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered. CONCLUSION: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced utilization. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events.

High-Dose 4-Factor Prothrombin Complex Concentrate for Warfarin-Induced Intracranial Hemorrhage.

BACKGROUND AND PURPOSE: The ideal dosing regimen of 4-factor prothrombin complex concentrate (4FPCC) after warfarin-induced intracranial hemorrhage (WICH) remains unclear. We sought to compare the safety and efficacy of the 4FPCC package insert dosing strategy (standard dose [SD]) with our institutional guideline for high-dose (HD) 4FPCC for patients with WICH. METHODS: We compared the percentage of SD and HD patients who achieved an international normalized ratio (INR) ≤1.3 at a single institution between January 2014 and July 2017. Additionally, we assessed hematoma expansion, recurrence of INR > 1.3, and occurrence of thrombotic events within 7 days of 4FPCC administration. RESULTS: Of 48 patients with WICH, 30 received SD and 18 received HD. The median baseline INR was 2.5 (2.0-3.8) for SD patients and 3.3 (2.5-5) for HD patients (P = .147). Successful achievement of an INR ≤ 1.3 after the initial 4FPCC dose was obtained in 70% of patients in the SD group and 94% of patients in the HD group (P = .124). A higher percentage of patients in the SD group had an INR > 1.3 at some point after admission (30% vs 6%; P = .053). There was a trend toward more hematoma expansion in the SD group, but this was not statistically significant (17% in the SD group vs 0% in HD group; P = .056). There were 2 thrombotic events: one deep vein thrombosis in each group (P = .243). CONCLUSIONS: High-dose 4FPCC appears to be more effective at lowering INR and preventing bleed expansion in patients with WICH, while maintaining a similar safety profile.

Case Report: Analytically Confirmed Severe Albenzadole Overdose Presenting with Alopecia and Pancytopenia.

Internet-facilitated self-diagnosis and treatment is becoming more prevalent, putting individuals at risk of toxicity when drugs are acquired without medical oversight. We report a patient with delusional parasitosis who consumed veterinary albendazole purchased on the Internet, leading to pancytopenia, transaminase elevation, and alopecia. A 53-year-old man was sent to the emergency department (ED) by his gastroenterologist because of abnormal laboratory results. The patient had chronic abdominal pain and believed he was infected with parasites. He purchased two bottles of veterinary-grade albendazole on the Internet, and over the 3 weeks before his ED visit, he consumed 113.6 g of albendazole (a normal maximal daily dose is 800 mg). Five days before admission, he noticed hair loss and a rash on his face. His examination was notable for significant scalp hair loss and hyperpigmentation along the jaw line. Laboratory studies were remarkable for pancytopenia (most notably a white blood cell count (WBC) of 0.4 × 103 cells/mm3, with an absolute neutrophil count (ANC) of 0 × 103 cells/mm3) and transaminase elevation (aspartate aminotransferase [AST] 268 IU/L, alanine aminotransferase [ALT] 89 IU/L). He developed a fever and was treated with antibiotics and colony-stimulating factors for presumed neutropenic bacteremia. Over the course of 1 week, his hepatic function normalized and his ANC increased to 3,000 × 103 cells/mm3. Serial albendazole and albendazole sulfoxide concentrations were measured in serum and urine by liquid chromatography-quadruple time-of-flight mass spectrometry. On day 2, his serum concentrations were 20.7 ng/mL and 4,257.7 ng/mL for albendazole and albendazole sulfoxide, respectively. A typical peak therapeutic concentration for albendazole sulfoxide occuring at 2-5 hours post-ingestion is 220-1,580 ng/mL. Known adverse effects of albendazole include alopecia, transaminase elevation, and neutropenia. Pancytopenia leading to death from septic shock is reported. In our patient, prolonged use of high-dose albendazole resulted in a significant body burden of albendazole and albendazole sulfoxide, leading to pancytopenia, transaminase elevation, and alopecia. He recovered with supportive therapy.

A retrospective analysis of the periprocedural management of oral anticoagulants in patients undergoing interventional radiology procedures.

Limited evidence is available to guide periprocedural management of oral anticoagulants in the setting of interventional radiology (IR) procedures. For direct oral anticoagulants, therapy interruption (TI) is based on medication half-life and procedural bleeding risk. Periprocedural management of warfarin includes INR monitoring, and possible bridging with parenteral anticoagulants. It is unknown if these recommendations apply to IR procedures. To evaluate bleeding complications and thromboembolic events following periprocedural management of the factor Xa (FXa) inhibitors or warfarin in patients undergoing IR procedures. We performed a retrospective, observational study at NYU Langone Health (NYULH) of all adult patients who underwent an IR procedure from January 2015 to July 2017 and were receiving apixaban, rivaroxaban, or warfarin. Patients who were pregnant or who had a mechanical heart valve were excluded. At NYULH, TI is not required for FXa inhibitors, and an INR < 3 is recommended for patients on warfarin undergoing low risk procedures. For moderate/high risk procedures, TI for 48 h or 72 h with reduced renal function, is recommended for FXa inhibitors, and an INR < 1.5 is recommended for patients on warfarin. We evaluated 350 IR procedures, with a total of 174 low bleeding risk and 176 moderate/high bleeding risk. The 30-day major bleeding rate was 0.9%, clinically relevant non-major bleeding rate was 3%, minor bleeding rate was 1% and thromboembolic event rate was 1%. The periprocedural oral anticoagulation management strategy at NYULH appears safe given the low 30-day incidence of bleeding and thromboembolic events.

Assessment of patients post reversal with idarucizumab.

Idarucizumab, a fully humanized Fab antibody fragment, is indicated for reversal of dabigatran's anticoagulant activity. Idarucizumab neutralizes the anticoagulant effects of dabigatran by binding to dabigatran and its metabolite. In the full analysis of 503 patients, idarucizumab fully reversed the anticoagulant effect of dabigatran in more than 98% of patients. Real-world clinical experience with idarucizumab for dabigatran reversal remains limited. We report 11 real-world clinical cases in which idarucizumab was administered for dabigatran reversal in the setting of bleed (bleeding cohort n = 5) or emergent procedure (emergent procedure cohort, n = 6). Coagulation tests and clinical outcomes were assessed before and after idarucizumab administration. Clinical outcomes included thromboembolic events and hemostasis. The median (IQR) aPTT (seconds) before versus after idarucizumab was 40.4 (36.1) versus 27.3 (6.2) (bleeding cohort) and 50.1 (13.4) versus 26.5 (8.1) (emergent procedure cohort). The median (IQR) INR before and after idarucizumab was 2.0 (1.1) versus 1.2 (0.1) (bleeding cohort) and 1.1 (0.5) versus 1.1 (0.3) (emergent procedure cohort). Hemostasis was achieved in 4/5 patients in the bleeding cohort and 5/6 patients in the emergent procedure cohort. Thrombotic events occurred in four patients with a median time (IQR) from idarucizumab administration of 7.4 (4.3-14.7) days. Idarucizumab achieved adequate dabigatran reversal as evident by normalization of aPTT, INR, and achieving hemostasis. However, our data demonstrates a high thrombotic risk associated with dabigatran reversal with idarucizumab than previously reported.

Anticoagulation prescribing patterns in patients with cancer.

Cancer is a known hypercoagulable state that leads to an increased risk of venous thromboembolism (VTE). Low molecular weight heparin remains the preferred anticoagulant for VTE in patients with cancer over vitamin K antagonist. However, the preferred anticoagulant in prevention of stroke and systemic embolism in atrial fibrillation (AF) in patients with cancer has yet to be determined. The direct oral anticoagulants (DOACs) are increasingly being utilized; however their role in cancer has only recently been investigated. The objective of this retrospective cohort was to describe real-world anticoagulation prescribing patterns in cancer patients at a large academic medical center between January 1, 2013 and October 31, 2016. We sought to assess the safety, tolerability, and efficacy of DOACs in patients with cancer for either VTE and/or AF. Patient demographic, clinical characteristics, as well as bleeding and thrombotic events were collected. There were 214 patients in our analysis, of which 71 patients (33%) received a DOAC [apixaban (n = 22), dabigatran (n = 17), and rivaroxaban (n = 32)]. There were fewer bleeding events and/or discontinuations in the DOAC group compared to enoxaparin (13 vs. 27, p = 0.022). There was no difference in major or minor bleeds or thromboembolic events in comparing DOAC to enoxaparin or DOAC to warfarin. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs compared to warfarin or enoxaparin in patients with cancer. DOACs may represent an alternative to warfarin or enoxaparin in patients with cancer for VTE and/or stroke reduction in AF.