Severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019 (COVID-19)-induced infection can be associated with a coagulopathy, findings consistent with infection-induced inflammatory ...changes as observed in patients with disseminated intravascular coagulopathy (DIC). The lack of prior immunity to COVID-19 has resulted in large numbers of infected patients across the globe and uncertainty regarding management of the complications that arise in the course of this viral illness. The lungs are the target organ for COVID-19; patients develop acute lung injury that can progress to respiratory failure, although multiorgan failure can also occur. The initial coagulopathy of COVID-19 presents with prominent elevation of D-dimer and fibrin/fibrinogen-degradation products, whereas abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are relatively uncommon in initial presentations. Coagulation test screening, including the measurement of D-dimer and fibrinogen levels, is suggested. COVID-19-associated coagulopathy should be managed as it would be for any critically ill patient, following the established practice of using thromboembolic prophylaxis for critically ill hospitalized patients, and standard supportive care measures for those with sepsis-induced coagulopathy or DIC. Although D-dimer, sepsis physiology, and consumptive coagulopathy are indicators of mortality, current data do not suggest the use of full-intensity anticoagulation doses unless otherwise clinically indicated. Even though there is an associated coagulopathy with COVID-19, bleeding manifestations, even in those with DIC, have not been reported. If bleeding does occur, standard guidelines for the management of DIC and bleeding should be followed.
We model the accretion of gas onto a population of massive primordial black holes in the Milky Way and compare the predicted radio and x-ray emission with observational data. We show that, under ...conservative assumptions on the accretion process, the possibility that O(10)M_{⊙} primordial black holes can account for all of the dark matter in the Milky Way is excluded at 5σ by a comparison with a Very Large Array radio catalog at 1.4 GHz and at ≃40σ by a comparison with a Chandra x-ray catalog (0.5-8 keV). We argue that this method can be used to identify such a population of primordial black holes with more sensitive future radio and x-ray surveys.
Direct oral anticoagulants (DOACs) have significantly improved the care of patients requiring anticoagulation. With similar or better efficacy and safety outcomes and easier use in the outpatient ...setting compared with the standard-of-care vitamin K antagonists and low molecular weight heparin, DOACs are now endorsed as first-line treatment of indications including prevention of stroke and systemic embolism in nonvalvular atrial fibrillation and treatment of venous thromboembolism. DOACs are easy-to-use oral agents that offer simple dosing and short half-lives, with no need to test levels because of the wide therapeutic window and limited drug-drug interactions. After almost a decade of DOAC use, the question of testing DOAC levels in certain clinical situations has become the focus of debate. Although guidance for using routine coagulation tests is available, these tests are inadequate for optimal care. DOAC-specific tests have been developed but have limited availability in Europe and less availability in the United States. None are licensed. DOAC testing may be useful in the setting of critical clinical situations such as life-threatening bleeding or need for emergent surgery, especially with the availability of DOAC reversal agents. Patients with characteristics that fall outside the normal range may benefit from the guidance that DOAC testing could offer. Obstacles to adopting DOAC testing have been raised, such as test reliability and staffing costs; however, these problems are rapidly being resolved. Further investigation of the role of DOAC testing is needed to explore its full potential and role in clinical practice.
Learning Objectives
Cite the current indications, basic clinical pharmacology, and rationale for development of the new oral anticoagulants.
Explain the potential risk for drug‐drug interactions ...between the new oral anticoagulants and drugs commonly used in cancer patients.
Indications for anticoagulation are common in patients with malignancy. Cancer patients have an increased risk of developing venous thromboembolic events or may have other indications for anticoagulation, such as atrial fibrillation. New oral anticoagulants (NOACs) are now available that offer increased options for anticoagulation beyond the traditional vitamin K antagonists and low molecular weight heparins that have long been the cornerstone of treatment. This review will focus on the three NOACs that are currently approved for use in the U.S.: the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors, apixaban and rivaroxaban. Oncologists are likely to encounter an increasing number of patients taking these agents at the time of their cancer diagnosis or to have patients who develop indications for anticoagulation during the course of their disease. The basic pharmacology, current clinical indications, and approach to the use of NOACs in the cancer patient will be reviewed.
New oral anticoagulants are now available that offer increased options for anticoagulation beyond the traditional vitamin K antagonists. In this report, the basic pharmacology, current clinical indications, and approach to the use of new oral anticoagulants in the cancer patient have been reviewed.
Abstract 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 out of 28 (10.7%) patients treated with apixaban met two out of three 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.
Cancer‐associated thrombosis (CAT) is a major cause of morbidity and mortality in patients with cancer. Over the past 2 decades, enormous advances have been made in the management of CAT. The growing ...evidence base informing practice has led to the publication of a number of guidelines and guidance documents on the diagnosis and treatment of CAT. The goal of this review is to examine the latest versions of evidence‐based guidelines, highlighting the differences and similarities in their methodology, their disease‐specific content, and recommendations for management. Our analysis shows that for most clinical topics, the different guidelines provide roughly similar management advice. However, there are a number of important clinical topics in CAT that are not currently covered by the existing guidelines. We think inclusion of these topics in future versions of the guidelines will facilitate ongoing efforts to optimize the care of patients with CAT.
Implications for Practice
Cancer‐associated thrombosis (CAT) is a common complication in patients with cancer. This review examines the differences and similarities of the current CAT guidelines methods and recommendations. Current guidelines largely agree on many aspects of CAT management. However, there are a number of topics in CAT that are not currently included in guidelines where evidence‐based guidance would be very helpful for clinicians. Coverage of these topics in future guidelines is encouraged to optimize clinical practice.
Numerous guidelines for cancer‐associated thromboembolism have been published. This review compares recommendations from the most recent cancer‐specific guidelines, identifying areas in which guidance is lacking.
Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma.
We conducted an open-label, multicenter, randomized phase 3 trial ...involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival.
At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval CI, 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 95% CI, 0.45 to 1.18; P=0.20) corrected. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity.
A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).
Hodgkin's lymphoma (HL) represents the most common subtype of malignant lymphoma in young people in the Western world. Most patients can be cured with modern treatment strategies, although ...approximately 20% will die after relapse or progressive disease. The histologic hallmark of the disease is the presence of the characteristic Hodgkin Reed-Sternberg (HRS) cells in classical HL and so-called lymphocyte-predominant (LP) cells in nodular lymphocyte-predominant HL. HL is unique among all cancers because malignant cells are greatly outnumbered by reactive cells in the tumor microenvironment and make up only approximately 1% of the tumor. Expression of a variety of cytokines and chemokines by the HRS and LP cells is believed to be the driving force for an abnormal immune response, perpetuated by additional factors secreted by reactive cells in the microenvironment that help maintain the inflammatory milieu. The malignant HRS and LP cells manipulate the microenvironment, permitting them to develop their malignant phenotype fully and evade host immune attack. Gene expression signatures derived from non-neoplastic cells correlate well with response to initial and subsequent therapies, reflecting their functional relevance. Recent biomarker studies have added texture to clinical outcome predictors, and their incorporation into prognostic models may improve our understanding of the biologic correlates of treatment failure. Moreover, recent preclinical and clinical studies have demonstrated that the tumor microenvironment represents a promising therapeutic target, raising hope that novel treatment strategies focused on the interface between malignant and reactive cells will soon emerge.
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