D-dimer Thresholds to Exclude Pulmonary Embolism among COVID-19 Patients in the Emergency Department: Derivation with Independent Validation.

OBJECTIVE: To derive and validate a D-dimer cutoff for ruling out pulmonary embolism (PE) in COVID-19 patients presenting to the emergency department (ED). METHODS: A retrospective cohort study was performed in an integrated healthcare system including 22 adult ED's between March 1, 2020, and January 31, 2021. Results were validated among patients enrolled in the RECOVER Registry, representing data from 154 ED's from 26 US states. Consecutive ED patients with laboratory confirmed COVID-19, a D-dimer performed within 48 h of ED arrival, and with objectively confirmed PE were compared to those without PE. After identifying a D-dimer threshold at which the 95% confidence lower bound of the negative predictive value for PE was higher than 98% in the derivation cohort, it was validated using RECOVER registry data. RESULTS: Among 3978 patients with a D-dimer result, 3583 with confirmed COVID-19 infection were included in the derivation cohort. Overall, PE incidence was 4.1% and a D-dimer cutoff of <2 µ/mL (2000 ng/mL) was associated with a NPV of 98.5% (95% CI = 98.0%-98.9%). In the validation cohort of 13,091 patients with a D-dimer, 7748 had confirmed COVID-19 infection, and the PE incidence was 1.14%. A D-dimer cutoff of <2 µ/mL was associated with a NPV of 99.5% (95% CI = 99.3%-99.7%). CONCLUSION: A D-dimer cutoff of <2 µ/ml was associated with a high negative predictive value for PE among patients with COVID-19. However, the resultant sensitivity for PE result at that threshold without pre-test probability assessment would be considered clinically unsafe.

Treatment of Cancer-Associated Venous Thromboembolism with Low-Molecular-Weight Heparin or Direct Oral Anticoagulants: Patient Selection, Controversies, and Caveats.

The treatment of venous thromboembolism (VTE) in patients with cancer is challenging because these patients have increased risks of both recurrent VTE and major bleeding, along with patient-specific and cancer-related factors that influence the approach to treatment. Historically, anticoagulant therapy with low-molecular-weight heparin (LMWH), given for both initial and long-term treatment, has been the preferred approach recommended by practice guidelines. Most recently, the National Comprehensive Cancer Network (NCCN) guidelines indicate that the direct oral anticoagulants (DOACs) apixaban, edoxaban, or rivaroxaban are preferred for patients without gastric or gastroesophageal lesions. DOACs have been associated with an increased risk of major bleeding in patients with gastrointestinal and possibly genitourinary cancers, and DOACs should either not be used (especially in those with intact intraluminal tumors) or be used with caution in patients with these cancers. Fatal or life-threatening bleeding occurs with similar frequency with DOACs or LMWH, and most major bleeding with DOACs can be managed with transfusion and standard measures. The patient's willingness and ability to comply with LMWH injections, and their treatment preference, should also be considered. Patients with cancer who have VTE should be treated with anticoagulation for a minimum of 6 months. Anticoagulation should be continued indefinitely while cancer is active or under treatment or if there are persistent risk factors for recurrent VTE. This article summarizes the evidence from clinical trials of LMWH and DOACs that underpins the NCCN guideline recommendations, addresses several controversies and caveats regarding anticoagulant treatment, and offers evidence-based, practical suggestions on patient selection for treatment with DOACs. IMPLICATIONS FOR PRACTICE: Several randomized trials support the addition of direct oral anticoagulants (DOACs) to the therapeutic armamentarium for cancer-associated venous thromboembolism (VTE). These agents come with unique risks and patient- and cancer-specific variables that must be evaluated during the course of a patient's cancer care. This narrative review discusses findings from clinical trials of low-molecular-weight heparin and DOACs for the treatment of cancer-associated VTE, evidence that supports the recent National Comprehensive Cancer Network guideline recommendations. A personalized approach to treatment is proposed that addresses patient selection for treatment with DOACs, factors that influence efficacy and safety, controversies and caveats, and suggestions for their resolution in clinical practice.

Extended Venous Thromboembolism Prophylaxis in Medically Ill Patients: An NATF Anticoagulation Action Initiative.

Hospitalized patients with acute medical illnesses are at risk for venous thromboembolism (VTE) during and after a hospital stay. Risk factors include physical immobilization and underlying pathophysiologic processes that activate the coagulation pathway and are still present after discharge. Strategies for optimal pharmacologic VTE thromboprophylaxis are evolving, and recommendations for VTE prophylaxis can be further refined to protect high-risk patients after hospital discharge. An early study of extended VTE prophylaxis with a parenteral agent in medically ill patients yielded inconclusive results with regard to efficacy and bleeding. In the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial, extended use of betrixaban halved symptomatic VTE, decreased hospital readmission, and reduced stroke and major adverse cardiovascular events compared with standard enoxaparin prophylaxis. Based on findings from APEX, the Food and Drug Administration approved betrixaban in 2017 for extended VTE prophylaxis in acute medically ill patients. In the Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER) study, extended use of rivaroxaban halved symptomatic VTE in high-risk medical patients compared with placebo. In 2019, rivaroxaban was approved for extended thromboprophylaxis in high-risk medical patients, thus making available a new strategy for in-hospital and post-discharge VTE prevention. To address the critical unmet need for VTE prophylaxis in medically ill patients at the time of hospital discharge, the North American Thrombosis Forum (NATF) is launching the Anticoagulation Action Initiative, a comprehensive consensus document that provides practical guidance and straightforward, patient-centered recommendations for VTE prevention during hospitalization and after discharge.

Evaluation of Dose-Reduced Direct Oral Anticoagulant Therapy.

BACKGROUND: Compared with vitamin K antagonists, direct-acting oral anticoagulants (DOACs) have fixed dosing, limited drug interactions, and do not require therapeutic drug level monitoring. Dose adjustments are recommended for moderate renal dysfunction, low body weight, and select drug interactions. OBJECTIVES: The aim of our study is to determine if DOAC dose reductions were appropriate based on the manufacturer labeling recommendations for each agent. We also followed patients' treatment outcomes. METHODS: We retrospectively reviewed patients administered a DOAC at a reduced dose between January 2011 and August 2014. The primary outcome was adherence to current manufacturer dose recommendations. The secondary outcome measures were the incidence of thromboembolic events or any bleeding episodes, regardless of severity, while on therapy. RESULTS: Of 224 patients included in the analysis, 43.3% of patients fit criteria for a dose adjustment according to manufacturer recommendations. Only 3 of 28 (10.7%) patients treated with apixaban met 2 out of 3 clinical criteria required for a dose reduction per manufacturer recommendations. Only 54.7% of rivaroxaban-treated patients and 32.2% of dabigatran-treated patients had renal insufficiency requiring a dose reduction. Half of our patient population received aspirin therapy, with 6.3% of patients on triple antithrombotic therapy (dual antiplatelet agents plus an anticoagulant). A past medical history significant for bleeding was prevalent in patients treated with a reduced-dose DOAC (32.1%, 20.4%, and 25.4% of patients in the apixaban-, rivaroxaban-, and dabigatran-treated groups, respectively). Thromboembolic events occurred in 10.7%, 3.6%, and 5.1% of patients in the apixaban, rivaroxaban, and dabigatran groups, respectively. Frequency of bleeding complications, regardless of severity, was 17.9%, 18.2%, and 23.7% of patients in the apixaban, rivaroxaban, and dabigatran groups, respectively. CONCLUSION: We found that dose-adjusted DOAC therapy was often prescribed in a dose that was lower than package insert recommendations.

Comparing clinicians' use of an anticoagulation management service and usual care in ambulatory oncology.

PURPOSE: There is no consensus in the oncology community about the optimal model for anticoagulation management of ambulatory cancer patients. To understand oncologists' preferences regarding anticoagulation management, we compared the characteristics of patients referred to an oncology-oriented anticoagulation management service with "usual care" patients managed by the patient's primary oncologist. METHODS: We performed a retrospective medical record review of ambulatory oncology patients' anticoagulation care at a comprehensive cancer center. We examined the characteristics of 33 patients anticoagulated before implementation of a dedicated oncology anticoagulation management service. We compared this group with 33 patients managed by the anticoagulation management service and with 39 usual care patients managed by the primary oncologist after the anticoagulation management service was created. We also examined differences in laboratory test utilization, time in the therapeutic range (for patients anticoagulated with warfarin), and anticoagulation-related adverse events during a 3-month assessment period. RESULTS: Anticoagulation management service patients were more likely to be treated for hematologic malignancies, use erythropoietin stimulating agents, and require warfarin management for previous venous thromboembolic disease compared to usual care patients. In contrast, oncologists were more likely to manage anticoagulation care of patients with advanced solid tumors undergoing active chemotherapy. Anticoagulation management service and usual care patients on warfarin therapy had comparable time in the therapeutic range and complication rates. CONCLUSION: Oncologists selectively referred patients to the anticoagulation management service. Anticoagulation management service patients' warfarin control and complication rates were comparable to care provided by the primary oncologist, suggesting that an oncology-specific anticoagulation management service may be a feasible and effective option for anticoagulation management of ambulatory oncology patients.