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There are limited data about the frequency of urgent surgical emergencies among patients receiving oral anticoagulants (OACs). We conducted a systematic literature review of Medline and EMBASE for published English-language articles of adult patients receiving oral anticoagulant treatment (vitamin K antagonists, apixaban, dabigatran, edoxaban, rivaroxaban) that reported on patients experiencing unplanned emergent or urgent surgery/procedure or trauma. Randomized trials, observational studies, and case series (50-100 cases) were included. The primary outcome was the frequency of unplanned urgent surgery or invasive procedures among OAC-treated patients with a focus on those not precipitated by the presence of major bleeding. The protocol was not registered. Funding was provided by Covis Pharmaceuticals. The search yielded 1367 potential studies of which 34 were included in the final review. One study reported the rate of urgent surgery/procedures among a large cohort of patients treated with dabigatran or warfarin for atrial fibrillation (~ 1% per year). Another study reported the rate of bleeding or urgent surgery among OAC-treated patients experiencing a fracture or trauma (0.489% per patient-year). The remaining 32 studies were cohorts of OAC-treated patients who received reversal or hemostatic therapies for major bleeding or urgent surgery. A median of 28.8% of these patients underwent surgery or invasive procedure. Urgent surgery appears to be a common, yet understudied complication during OAC treatment potentially associated with high rates of adverse outcomes. With increased eligibility for OACs, future studies evaluating the management and outcomes in this setting are needed.

Background: Fatal bleeding is a component of the primary safety outcome in most studies evaluating anticoagulation for venous thromboembolism (VTE), but a standardized definition for fatal bleeding is lacking. Objectives: To summarize definitions of fatal bleeding and describe the range of case-fatality rates of major bleeding in VTE studies. Methods: MEDLINE, Embase, and CENTRAL databases were searched from January 2008 to July 2021 for prospective studies that enrolled patients with VTE and evaluated the efficacy/safety of anticoagulation for VTE treatment or included fatal or major bleeding as primary outcome. Two authors independently performed study selection and data extraction. The primary outcome was the definition of fatal bleeding. The secondary outcome was the case-fatality rate of major bleeding. Data were analyzed using descriptive statistics. Results: Of 4911 records identified, we included 132 articles representing 89 distinct studies. Twenty-seven (20%) articles and 7 of 89 (8%) studies reported a definition of fatal bleeding. Overall, we identified 3 different types of definitions that were either on the basis of a specific time interval between bleeding and death, bleeding location (intracranial) or clinical presentation (hemodynamic deterioration), or mainly relied on the judgment of the adjudication committee to determine the cause of death. The case-fatality rate of major bleeding ranged from 0 to 60% (median, 9.1%; interquartile range, 2.8%-18%). Conclusion: Less than 10% of studies assessing anticoagulant treatment for VTE reported a definition for fatal bleeding. The lack of a (standardized) definition for fatal bleeding may lead to inaccurate estimates of the risk of fatal bleeding, particularly when compared across studies.

Education of patients is thought to be key to high-quality oral anticoagulant (OAC) medication management. Theoretically, improving patients' knowledge should improve their self-management skills and adherence. The study's objective was to explore the opinions of healthcare providers and patients on the desired content and format of patient education on OACs, in addition to perceived barriers to high-quality patient education.We applied qualitative descriptive methods in a focus group study on OAC management. Five focus group discussions were conducted in two health regions in Southwestern Ontario from 2017 to 2018 with 19 patients, 7 caregivers and 16 healthcare providers (physicians, nurses and pharmacists). During the focus groups, participants discussed their experiences with OAC education and made suggestions about the content and format for patient education on OACs. Transcripts were analysed using conventional content analysis.We identified the five themes of patient education on OAC management: content of OAC education (rationale, risk and appropriate drug administration methods), the best times for providing OAC education (time of OACs initiation along with continuing education), preferred education delivery strategies (case management targeted patient information summaries from authoritative sources such as Thrombosis Canada and video education), patient and community pharmacist engagement in OAC education, and perceived barriers to optimal patient education (patients depending too much on their healthcare providers for advice, the limited time patients spend with healthcare providers, gaps in clear communication between providers and the lack of a nationally or provincially coordinated OAC management programme).Our findings suggest that patients, caregivers and healthcare providers support the need for education on OACs, including for patients taking DOACs. Specific important content and proper education format are needed. The optimal combination of content, format, duration, timing and sources for OAC education requires further research.

Gastrointestinal (GI) bleeding is the most frequent single site of oral anticoagulant (OAC)-associated major bleeding. Patients with major GI bleeding experience morbidity and a substantial risk of short-term all-cause mortality up to 10%. While OACs are frequently discontinued during acute bleeding, there is substantial uncertainty about whether, when, and how OACs should be resumed after bleeding has resolved. Limited evidence suggests a lower risk of thromboembolism and death, and a higher risk of recurrent bleeding with OAC resumption. However, the absolute risks and optimal timing of anticoagulation remain uncertain based on these observational studies at risk of bias, particularly due to baseline confounding. In addition to an individualized approach to determining the benefits and harms of treatment decisions informed by the best available evidence about thrombosis and recurrent bleeding, discussions should meaningfully incorporate patient values and preferences. The objective of this review is to provide a framework for decision-making by summarizing the epidemiology and clinical outcomes of OAC-associated GI bleeding, providing an approach for assessment and risk stratification for OAC resumption and its timing, and outlining strategies for the prevention of recurrent GI bleeding.

Background: COVID-19–related acute illness is associated with an increased risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation in patients with COVID-19. Methods: ASH formed a multidisciplinary guideline panel that included patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process and performed systematic evidence reviews (through November 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 as part of the living phase of these guidelines. Results: The panel made one additional recommendation. The panel issued a conditional recommendation in favor of therapeutic-intensity over prophylactic-intensity anticoagulation in patients with COVID-19–related acute illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of risk of thrombosis and bleeding. The panel also noted that heparin (unfractionated or low molecular weight) may be preferred because of a preponderance of evidence with this class of anticoagulants. Conclusion: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation in patients with COVID-19–related acute illness.

Background: COVID-19–related critical illness is associated with an increased risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for patients with COVID-19. Methods: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing systematic evidence reviews (up to January 2022). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 and May 2021 as part of the living phase of these guidelines. Results: The panel made 1 additional recommendation: a conditional recommendation for the use of prophylactic-intensity over therapeutic-intensity anticoagulation for patients with COVID-19–related critical illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of thrombotic and bleeding risk. Conclusions: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation for patients with COVID-19–related critical illness.

Introduction Oral anticoagulant (OAC) intervention trials have typically included clinical event outcomes. However, there is no standard list of outcomes to be used in OAC research. This study aimed to describe and classify the outcomes used in recent prospective clinical studies involving OACs. Materials and methods We searched MEDLINE, EMBASE, and CINAHL databases from January 2009 to July 2019 for prospective studies with an intervention or control group that included one or more oral anticoagulants. We abstracted details about each included study and the outcomes used from the study report and its accompanying protocol. Using the Core Outcome Measures in Effectiveness Trials (COMET) Initiative recommendations, we categorised each outcome into one of five domains (mortality/survival, physiological/clinical, life impact, resource use, and adverse events). Our primary outcome was the prevalence of use of an outcome domain across studies. Results We included 70 prospective studies, including 52 randomized controlled trials and 18 prospective cohort studies. A total of 121 different outcomes were reported. The COMET domains were represented in the 70 studies as follows: mortality (63/70, 90.0%); physiological/clinical domain (70/70, 100%), life impact domain (43/70, 61.4%), resource use domain (26/70, 37.1%), and adverse events domain (55/70, 78.6%). Conclusion Outcome reporting in prospective studies of OACs more frequently concentrates on mortality, physiological/clinical domains, and adverse events compared to life impact and resource utilization domains, the latter uncommonly used. A priority for future research includes developing a core outcome set (COS) for OAC research that represents all domains.

Background Data on resuming oral anticoagulants (OACs) after bleeding are primarily from studies involving patients given warfarin, with few data on direct OACs (DOACs). We aimed to characterize prescribing patterns for OACs after OAC-related bleeding and compare the rates of bleeding, thrombosis and mortality in patients who resumed either type of OAC with those who did not. Methods We conducted a population-based cohort study of adults aged 66 years or older who were admitted to hospital for bleeding while receiving OACs from Apr. 1, 2012, to Mar. 31, 2017, using linked administrative health databases from Ontario. We used competing risk methods to calculate cause-specific adjusted hazard ratios (HRs) for thrombosis, bleeding and mortality with resumption of OACs adjusted as a time-varying covariate. We determined time to OAC resumption using the Kaplan-Meier method. Results We included 6793 patients with gastrointestinal (n = 4297, 63.3%), intracranial (n = 805, 11.9%) or other bleeding (n = 1691, 25.0%). At cohort entry, 3874 patients (57.0%) were prescribed warfarin and 2919 patients (43.0%) were prescribed a DOAC. The most common indication for OAC was atrial fibrillation (n = 5557, 81.8%), followed by venous thromboembolism (n = 1367, 20.1%). Oral anticoagulants were resumed in 4792 patients (70.5%) within 365 days of the index bleed. The median time to resumption was 46 (interquartile range 6-550) days. We found that resuming OAC was associated with reduced rates of thrombosis (adjusted HR 0.60, 95% confidence interval [CI] 0.50-0.72) and mortality (adjusted HR 0.54, 95% CI 0.48-0.60), and an increased rate of rebleeding (adjusted HR 1.88, 95% CI 1.64-2.17). Interpretation We found that resuming OAC is associated with a reduction in thrombosis and mortality but an increase in bleeding. Randomized controlled trials that evaluate the net benefit of strategies for resumption of OAC after a bleeding event are warranted.

Introduction Bariatric surgery patients experience an increased risk of venous thromboembolism (VTE), however, the optimal dose of low-molecular-weight heparin for VTE prophylaxis remains uncertain. Currently, St. Joseph's Healthcare Hamilton utilizes a weight-adjusted tinzaparin dosage (50 to 75 units/kg rounded to nearest pre-filled syringe) for postoperative VTE prophylaxis. Objectives This study analyzed the safety of weight-adjusted tinzaparin for VTE prophylaxis in bariatric surgery patients weighing ≥160 kg. Methods This was a retrospective study involving patients weighing ≥160 kg that underwent bariatric surgery from September 2015 to September 2019. Patients received a single dose of weight-adjusted subcutaneous unfractionated heparin (UFH) [5000 or 7500 IU] immediately prior to surgery, subcutaneous UFH [5000 IU, 7500 IU, or unspecified] immediately postoperatively, and either 10,000 or 14,000 IU of tinzaparin, beginning on the day after surgery, for 10 days. Intra-operative sequential compression devices could be used at the attending surgeon's discretion. Occurrence of VTE and major bleeding within 30 days of surgery were assessed. Results A total of 389 patients were included for analysis, all patients received in-hospital follow-up while 349 patients had also 30-day follow-up. For the primary safety and efficacy analysis of in-hospital events, VTE and major bleeding rates were 0.26% [95% CI 0.01%–1.44%] (1/389) and 0.77% [95% CI 0.21%–2.24%] (3/389) respectively. For patients with 30-day follow-up VTE and major bleeding rates were 0.57% [95% CI 0.1%–2.07%] (2/349) and 1.43% [95% CI 0.61%–3.3%] (5/349) respectively. Conclusions Weight-adjusted tinzaparin was associated with a low risk of bleeding and VTE events, supporting its use for VTE prophylaxis for patients weighing ≥160 kg.

International audience; Patients with acute venous thromboembolism (VTE) require anticoagulant therapy to prevent recurrent VTE and death, which exposes them to an inherent increased risk of bleeding. Identification of patients at high risk of bleeding, and mitigating this risk, is an essential component of the immediate and long-term therapeutic management of VTE. The bleeding risk can be estimated by either implicit judgment, weighing individual predictors (clinical variables or biomarkers), or by risk prediction tools developed for this purpose. Management of bleeding risk in clinical practice is, however, far from standardized. International guidelines are contradictory and lack clear and consistent guidance on the optimal management of bleeding risk. This report of the ISTH subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease summarizes the evidence on the prediction of bleeding in VTE patients. We systematically searched the literature and identified 34 original studies evaluating either predictors or risk prediction models for prediction of bleeding risk on anticoagulation in VTE patients. Based on this evidence, we provide recommendations for the standardized management of bleeding risk in VTE patients.

Objectives(1) Describe how the risk of major adverse cardiovascular events (MACE) in individuals with chronic myeloid leukaemia (CML) has evolved; (2) evaluate the risk of MACE associated with the prescription of different CML tyrosine kinase inhibitors (TKI).MethodsA population-based retrospective study including all patients (n=4238) diagnosed with CML in Ontario, Canada between 1986 and 2017 and and age-matched and sex-matched individuals who received healthcare but who did not have CML (controls: n=42 380). The cohort was divided into those entering before 2001 vs from 2001 onwards (when TKIs were introduced). We developed competing risks models to compare time-to-event in CML cases versus controls. We adjusted for baseline comorbidities and present subdistribution HRs and 95% CIs. The relationship between TKI use and MACE was assessed by logistic regression.ResultsBefore 2001 and from 2001 on, patients with CML had a higher crude incidence of MACE than patients without CML (19.8 vs 15.3 and 20.3 vs 12.6 per 1000 person-years, respectively). After adjustment for cardiovascular risk factors, patients with CML had a lower subdistribution hazard for MACE (0.59, 95% CI 0.46 to 0.76) before 2001; but from 2001, the adjusted subdistribution HR for MACE (1.27, 95% CI 0.96 to 1.43) was similar to age-matched and sex-matched patients. The incidence (9.3 vs 13.8 per 1000 person-years) and subdistribution hazard for cardiovascular death (0.43, 95% CI 0.36 to 0.52) were lower in patients with CML than controls before 2001. From 2001 on, the incidence (6.3 vs 5.4 per 1000 person-years) and subdistribution hazard for cardiovascular death (0.99, 95% CI 0.84 to 1.18) were similar to age-matched and sex-matched patients without CML with a higher risk of cerebrovascular events (8.6 vs 5.6 per 1000 person-years; 1.35, 95% CI 1.00 to 1.83) and peripheral arterial events (6.9 vs 3.0 per 1000 person-years; 1.66 95% CI, 1.15 to 2.39) in patients with CML than patients without CML. Compared with imatinib, there was no difference in the risk of MACE among those prescribed dasatinib (OR 0.67, 95% CI 0.41 to 1.10) or nilotinib (OR 1.22, 95% CI 0.70 to 1.97).ConclusionsIn a contemporary CML population, the risk of MACE and cardiovascular death is at least as high as among age-matched and sex-matched patients without CML and may be higher for cerebrovascular and peripheral arterial events. No difference in the risk of MACE between imatinib, dasatinib and nilotinib was observed.

Background We aimed to establish diagnostic criteria for bleeding independently associated with mortality after noncardiac surgery (BIMS) defined as bleeding during or within 30 days after noncardiac surgery that is independently associated with mortality within 30 days of surgery, and to estimate the proportion of 30-day postoperative mortality potentially attributable to BIMS. Methods This was a prospective cohort study of participants ≥45 yr old having inpatient noncardiac surgery at 12 academic hospitals in eight countries between 2007 and 2011. Cox proportional hazards models evaluated the adjusted relationship between candidate diagnostic criteria for BIMS and all-cause mortality within 30 days of surgery. Results Of 16 079 participants, 2.0% (315) died and 36.1% (5810) met predefined screening criteria for bleeding. Based on independent association with 30-day mortality, BIMS was identified as bleeding leading to a postoperative haemoglobin Conclusions Bleeding independently associated with mortality after noncardiac surgery (BIMS), defined as bleeding that leads to a postoperative haemoglobin Clinical trial registration NCT00512109.

Key Points This toolkit contains standardized customizable thrombosis-related data elements for incorporation into COVID-19 studies. Standardization can enhance the quality of data collection, create efficiency, and facilitate comparison of results and pooling of data sets., Thrombosis has emerged as an important complication of coronavirus disease 2019 (COVID-19), particularly among individuals with severe illness. However, the precise incidence of thrombotic events remains uncertain due to differences in study design, patient populations, outcome ascertainment, event definitions, and reporting. In an effort to overcome some of these challenges and promote standardized data collection and reporting in clinical studies, the American Society of Hematology Research Collaborative COVID-19 Non-Malignant Hematology Task Force, in collaboration with the International Society on Thrombosis and Haemostasis COVID-19 Task Force, developed sets of data elements in the following domains: venous thromboembolism, myocardial infarction, stroke/transient ischemic attack, peripheral arterial thrombosis, bleeding, laboratory investigations, and antithrombotic therapy. Data elements in each of these domains were developed with 3 levels of detail to facilitate their incorporation into studies evaluating a range of interventions and outcomes. Previously published data elements were included where possible. The use of standardized variables in a range of clinical studies can enhance the quality of data collection, create efficiency, enhance comparison of results across studies, and facilitate future pooling of data sets., Visual Abstract

Iron deficiency is a common consequence of bariatric surgery and frequently leads to anemia. Our study reports the incidence and predictors of iron deficiency, iron deficiency anemia (IDA), and IV iron use after bariatric surgery. We conducted a retrospective study of all adult patients who underwent bariatric surgery from January to December 2012 at the regional bariatric surgery center in Hamilton, Ontario, Canada, and were followed for at least 6 months. Time-to-event data were presented as Kaplan-Meier curves. Cox regression analysis was used to identify outcome predictors. A total of 388 patients met the inclusion criteria. Iron deficiency, IDA, and the use of IV iron were reported in 43%, 16%, and 6% of patients, respectively, with a mean follow-up of 31 months. The cumulative incidence of iron deficiency and IDA increased with longer follow-up, and there was a significant increase in IV iron use starting 3 years after surgery. Malabsorptive procedures (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.20-3.06; P = .006) and low baseline ferritin (HR, 0.96; 95% CI, 0.95-0.97; P < .001) were associated with an increased risk of iron deficiency. Young age (HR, 0.90; 95% CI, 0.82-0.99; P = .028), baseline anemia (HR, 19.6; 95% CI, 7.85-48.9; P < .001), and low baseline ferritin (HR, 0.96; 95% CI, 0.95-0.98; P < .001) were associated with an increased risk of IDA. Our results suggest that IDA is a delayed consequence of bariatric surgery and that preoperative assessment of patient risk may be possible.

Ty J. Gluckman, MD, FACC, Chair Niti R. Aggarwal, MD, FACC Nicole M. Bhave, MD, FACC Gregory J. Dehmer, MD, MACC Olivia N. Gilbert, MD, MSc, FACC Chayakrit Krittanawong, MD Dharam J. Kumbhani, MD, SM, FACC Javier A. Sala-Mercado, MD, PhD Andrea L. Price, CPHQ, RCIS, AACC David E.

Aims To examine the rates of venous thromboembolism (VTE) in high-income, upper middle-income, and lower middle/low-income countries (World Bank Classification). Methods and results We examined the rates of VTE in high-income, upper middle-income, and lower middle/low-income countries (World Bank Classification) in a cohort derived from four prospective international studies (PURE, HOPE-3, ORIGIN, and COMPASS). The primary outcome was a composite of pulmonary embolism, deep vein thrombosis, and thrombophlebitis. We calculated age- and sex-standardized incidence rates (per 1000 person-years) and used a Cox frailty model adjusted for covariates to examine associations between the incidence of VTE and country income level. A total of 215 307 individuals (1.5 million person-years of follow-up) from high-income (n = 60 403), upper middle-income (n = 42 066), and lower middle/low-income (n = 112 838) countries were included. The age- and sex-standardized incidence rates of VTE per 1000 person-years in high-, upper middle-, and lower middle/low-income countries were 0.87, 0.25, and 0.06, respectively. After adjusting for age, body mass index (BMI), smoking, antiplatelet therapy, anticoagulant therapy, education level, ethnicity, and incident cancer diagnosis or hospitalization, individuals from high-income and upper middle-income countries had a significantly higher risk of VTE than those from lower middle/low-income countries [hazard ratio (HR) 3.57, 95% confidence interval (CI) 2.40–5.30 and HR 2.27, 95% CI 1.59–3.23, respectively]. The effect of country income level on VTE risk was markedly stronger in people with a lower BMI, hypertension, diabetes, non-White ethnicity, and higher education. Conclusion The rates of VTE are substantially higher in high-income than in low-income countries. The factors underlying the increased VTE risk in higher-income countries remain unknown.

BackgroundCOVID-19–related acute illness is associated with an increased risk of venous thromboembolism (VTE).ObjectiveThese evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE.MethodsASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development, and evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment.ResultsThe panel agreed on 1 additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 who are discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation.ConclusionsThis recommendation was based on very low certainty in the evidence, underscoring the need for high-quality randomized controlled trials assessing the role of postdischarge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.

OBJECTIVE To identify prognostic factors for the development of venous thromboembolism in the ICU. DATA SOURCES We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception to March 1, 2021. STUDY SELECTION We included English-language studies describing prognostic factors associated with the development of venous thromboembolism among critically ill patients. DATA EXTRACTION Two authors performed data extraction and risk-of-bias assessment. We pooled adjusted odds ratios and adjusted hazard ratios for prognostic factors using random-effects model. We assessed risk of bias using the Quality in Prognosis Studies tool and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. DATA SYNTHESIS We included 39 observational cohort studies involving 729,477 patients. Patient factors with high or moderate certainty of association with increased odds of venous thromboembolism include older age (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29 per 10 yr), obesity (adjusted odds ratio, 1.25; 95% CI, 1.18-1.32), active malignancy (adjusted odds ratio, 1.70; 95% CI, 1.18-2.44), history of venous thromboembolism (adjusted odds ratio, 4.77; 95% CI, 3.42-6.65), and history of recent surgery (adjusted odds ratio, 1.77; 95% CI, 1.26-2.47). ICU-specific factors with high or moderate certainty of association with increased risk of venous thromboembolism include sepsis (adjusted odds ratio, 1.41; 95% CI, 1.12-1.78), lack of pharmacologic venous thromboembolism prophylaxis (adjusted odds ratio, 1.80; 95% CI, 1.14-2.84), central venous catheter (adjusted odds ratio, 2.93; 95% CI, 1.98-4.34), invasive mechanical ventilation (adjusted odds ratio, 1.74; 95% CI, 1.36-2.24), and use of vasoactive medication (adjusted odds ratio, 1.86; 95% CI, 1.23-2.81). CONCLUSIONS This meta-analysis provides quantitative summaries of the association between patient-specific and ICU-related prognostic factors and the risk of venous thromboembolism in the ICU. These findings provide the foundation for the development of a venous thromboembolism risk stratification tool for critically ill patients.

Background: COVID-19–related critical illness is associated with an increased risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19–related critical illness who do not have confirmed or suspected VTE. Methods: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by performing systematic evidence reviews (up to 5 March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021. Results: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19–related critical illness who do not have confirmed or suspected VTE. Conclusions: This recommendation was based on low certainty in the evidence, which underscores the need for additional high-quality, randomized, controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence regarding predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of nonanticoagulant therapies (eg, antiviral agents, corticosteroids) on thrombotic risk.

Objectives Obesity is associated with increased risks of atrial fibrillation (AF) and venous thromboembolism (VTE) for which anticoagulation is commonly used. However, data on the efficacy and safety of oral anticoagulants in patients with morbid obesity are limited. Methods We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) for AF or VTE in patients with morbid obesity. Results We included three randomized controlled trials (5 studies) and 18 observational studies in adult patients with a body weight ≥120 kg, body mass index ≥40 kg/m2, or classified as morbid obesity who received DOACs or VKAs for AF or VTE (N = 77,687). The primary efficacy outcome was stroke/systemic embolism or recurrent VTE, and the primary safety outcome was major bleeding. DOACs were associated with a pooled incidence rate of stroke/systemic embolism of 1.16 per 100 person-years, compared to 1.18 with VKAs. The incidence of recurrent VTE on DOACs was 3.83 per 100 person-years, compared to 6.81 on VKAs. In both VTE and AF populations, DOACs were associated with lower risks of major bleeding compared to VKAs. However, all observational studies had moderate to serious risks of bias. Conclusion Patients with morbid obesity on DOACs had similar risks of stroke/systemic embolism, lower rates of recurrent VTE, and major bleeding events compared to those on VKAs. However, the certainty of evidence was low given that studies were mostly observational with high risk of confounding.

Purpose Trauma patients are at high risk of venous thromboembolism (VTE). We summarize the efficacy and safety of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) for the prevention of VTE in trauma patients. Methods We searched six databases from inception through March 12th, 2021. We included randomized controlled trials (RCTs) or observational studies comparing LMWH vs UFH for thromboprophylaxis in adult trauma patients. We pooled effect estimates across RCTs and observational studies separately, using random-effects model and inverse variance weighting. We assessed risk of bias using the Cochrane tool for RCTs and the ROBINS-I tool for observational studies and assessed certainty of findings using GRADE methodology. Results We included 4 RCTs (879 patients) and 8 observational studies (306,747 patients). Based on pooled RCT data, compared to UFH, LMWH reduces deep vein thrombosis (DVT) (relative risk [RR] 0.67, 95% confidence interval [CI] 0.50 to 0.88, moderate certainty) and VTE (RR 0.68, 95% CI 0.51 to 0.90, moderate certainty). As compared to UFH, LMWH may reduce pulmonary embolism (adjusted odds ratio from pooled observational studies (aOR) 0.56 (95% CI 0.50 to 0.62) and mortality (aOR from pooled observational studies 0.54, 95% CI 0.45 to 0.65), though based on low certainty evidence. There was an uncertain effect on adverse events (RR from pooled RCTs 0.80, 95% CI 0.48 to 1.33, very low certainty) and heparin induced thrombocytopenia (RR from pooled RCTs 0.26 (95% CI 0.03 to 2.38, very low certainty). Conclusion Among adult trauma patients, LMWH is superior to UFH for DVT and VTE prevention and may additionally reduce pulmonary embolism and mortality. The impact on adverse events and heparin induced thrombocytopenia is uncertain.

Background Anemia is common in critically ill patients and associated with adverse outcomes. Phlebotomy associated with laboratory testing is a potentially modifiable contributor. This study aims to 1) characterize the blood volume taken for laboratory testing, and 2) explore the effect of blood loss on red blood cell (RBC) transfusion and anemia in adult intensive care unit (ICU) patients. Methods Using a transfusion research database, we retrospectively reviewed consecutively admitted patients to four medical-surgical ICUs in Hamilton, Ontario, Canada. The primary outcome was estimated blood loss for laboratory testing during ICU admission. Secondary outcomes were hemoglobin (Hb) of 90 g/L or less and RBC transfusion. Results Among the 7273 patients included, the median blood volume per patient taken for laboratory testing during their ICU stay was 213 mL (interquartile range [IQR], 133-382 mL). On ICU admission, median Hb was 97 g/L (IQR, 82-116 g/L). An Hb of 90 g/L or less occurred in 67.0% of patients during their ICU stay. Median Hb on ICU discharge adjusted for RBC transfusion was 84 g/L (IQR, 58-105 g/L). RBC transfusion was administered to 47.5% of patients, who received a median of 3 units (IQR, 2-7 units). Cumulative blood loss due to laboratory testing from Day 2 to Day 7 of ICU admission was independently associated with RBC transfusion (hazard ratio, 2.28 for each 150-mL increment; 95% confidence interval, 2.02-2.59). Conclusions Blood loss for laboratory testing is substantial in ICU patients and significantly associated with RBC transfusion. Strategies to reduce blood loss from laboratory testing represents an area for further investigation.

Bleeding is the main complication of oral anticoagulant (OAC) therapy, with major bleeds occurring in about 2% to 4% of OAC-treated patients per year. Although direct oral anticoagulants (DOACs) reduce the risk of major, fatal, and intracranial hemorrhage, major DOAC-related bleeding is associated with substantial morbidity and mortality, with case-fatality rates of 8% to 15% reported. Specific reversal agents for dabigatran (idarucizumab) and factor Xa inhibitors (andexanet) correct laboratory indices of anticoagulant effect. Clinical studies suggest that the majority of patients receiving these agents for DOAC-associated major bleeds experience clinical hemostasis. However, uncertainty remains regarding the incremental benefit of these agents and prothrombin complex concentrates over supportive measures alone, based on cohort studies that lacked control groups. Similar methodologic limitations preclude firm conclusions regarding the harms associated with use of these agents. Importantly, patients with DOAC-related major bleeding have substantial short-term risks of thrombosis and mortality, emphasizing the need for individualized patient assessment and protocolized bleed management strategies that include assessment of candidacy for safe resumption of OACs. With expanding indications and increasing prevalence of DOAC-eligible patients, bleeding complications and their management represent an ever-greater major health problem.

A 77-year-old man with atrial fibrillation and a CHA2DS2Vasc score of 6 for hypertension, age, diabetes, and previous stroke is brought to the emergency department with decreased level of consciousness. He is anticoagulated with rivaroxaban (a direct oral factor Xa inhibitor [FXaI]) and received his last dose about 4 hours before presentation. Urgent computed tomography of the head shows intracerebral hemorrhage. Because of his previous stroke, the patient’s family is concerned about treating the bleed with pharmacological agents that may increase the risk of stroke. What are the risks of thrombosis and mortality related to the use of prothrombin complex concentrates (PCCs) and andexanet alfa for patients with direct oral FXaI-associated major bleeding?

Direct oral anticoagulants are associated with lower rates of bleeding than vitamin K antagonists, but life-threatening bleeding still occurs. Andexanet alfa is a catalytically inactive recombinant modified human factor Xa molecule that reverses the anticoagulant effect of direct and indirect acting factor Xa inhibitors. In the ANNEXA-4 study, treatment with andexanet was associated with a 92% reduction in median anti-Xa activity levels and excellent or good hemostasis in 82% of patients presenting with serious bleeding while receiving apixaban or rivaroxaban. In this review, we discuss the burden of bleeding in anticoagulated patients and the need for reversal agents, review the mechanism of action of andexanet and critically evaluate the evidence for its efficacy and safety.

Patients with cirrhosis are not only at an increased risk of bleeding but also at risk of venous thromboembolism (VTE). We sought to determine the clinical characteristics, management, and outcomes after VTE in patients with cirrhosis. We used the data from RIETE (Registro Informatizado de la Enfermedad TromboEmbolica), an international registry of patients with VTE, to compare the outcomes in patients with and without cirrhosis. Main outcomes included all-cause mortality, pulmonary embolism (PE)-related mortality, recurrent VTE, and bleeding. Among 43,611 patients with acute VTE, 187 (0.4%) had cirrhosis. Of these, 184 (98.4%) received anticoagulation for a median of 109 days (interquartile range [IQR]: 43–201 days), most commonly with enoxaparin (median dose: 1.77 [IQR: 1.38–2.00] mg/kg/day). Compared with patients without cirrhosis, those with cirrhosis had a higher rate of all-cause mortality (10.7 vs. 3.4%; odds ratio [OR]: 3.41; 95% confidence interval [CI]: 2.03–5.46) and fatal bleeding (2.1 vs. 0.2%; OR: 13.94; 95% CI: 3.65–37.90) but similar rates of fatal PE (0.5 vs. 0.5%; OR: 1.17; 95% CI: 0.03–6.70). Patients with cirrhosis had a higher rate of all-cause mortality per 100 patient-years of follow-up (58.9 vs. 16.0; hazard ratio [HR]: 3.70; 95% CI: 2.69–4.91). One-year hazard ratio of clinically relevant bleeding (HR: 2.86; 95% CI: 1.91–4.27), fatal bleeding (HR: 8.51; 95% CI: 3.5–20.7), or recurrent VTE (HR: 2.08; 95% CI: 1.00–4.36) was higher in patients with cirrhosis. Cirrhosis is a challenging comorbidity in patients with VTE. Most patients were treated with anticoagulation and had an elevated risk of recurrence, similar risk of fatal PE, and a very high risk of bleeding including fatal bleeds.

Background Antifibrinolytic agents such as tranexamic acid (TXA) are commonly used as adjunctive therapies to prevent and treat excessive bleeding. In non-surgical settings, TXA is known to reduce bleeding related mortality. However, impact of TXA use on thrombosis is uncertain. Methods We systematically searched the MEDLINE, EMBASE, and CENTRAL databases from January 1985 to August 2018. Studies with the following characteristics were included: (i) RCT design; (ii) compared systemic (oral or intravenous) TXA for prevention or treatment of bleeding for non-surgical indications and placebo or no TXA, and (iii) reported thrombotic events or mortality. A Mantel-Haenzel, random-effects model was used to calculate risk ratios, and risk of bias was assessed using the Cochrane risk of bias tool. Results Our search identified 22 studies representing 49,538 patients. Those receiving TXA had a significantly lower risk of death from any cause (RR = 0.92; 95% CI = 0.87–0.98; I2 = 0%). There was no significant increase in the risk of stroke (RR = 1.10; 95% CI = 0.68–1.78; I2 = 31%), myocardial infarction (RR = 0.88; 95% CI = 0.43–1.84; I2 = 46%), pulmonary embolism (RR = 0.97; 95% CI = 0.75–1.26; I2 = 0%), or deep vein thrombosis (RR = 0.99; 95% CI = 0.70–1.41; I2 = 0%) from use of TXA. The results were similar when restricted to studies at low risk of bias. Conclusions In our systematic review and meta-analysis, the use of tranexamic acid reduced all-cause mortality without increased risk of venous or arterial thrombotic complications.

BACKGROUND Right ventricular (RV) dysfunction predicts worse outcomes in acute pulmonary embolism (PE). Because computed tomography (CT) pulmonary angiography visualizes cardiac structures, it is a potential method for assessing RV function without the delays associated with inpatient echocardiography. OBJECTIVES We conducted a systematic review and meta-analysis to assess the diagnostic accuracy of CT scan findings for detecting RV dysfunction compared with echocardiography. METHODS We searched MEDLINE and EMBASE from inception to April 2020 for studies comparing RV dysfunction on CT scan with echocardiography standard. Study quality was assessed with the QUADAS-2 risk of bias tool. Meta-analysis was performed using a bivariate mixed effects regression framework. RESULTS After screening, 26 studies (3508 patients) were included. In a pooled analysis, septal deviation (5 studies; 459 patients) had a sensitivity of 0.31 (95% CI 0.25-0.38; I2 = 0%), specificity of 0.98 (95% CI 0.90-1.00; I2 = 59.4%), and positive likelihood ratio of 13.6 (95% CI 3.1-60.4) for RV dysfunction compared with echocardiography. The pooled sensitivity of increased RV/left ventricular ratio (21 studies; 3111 patients) was 0.83 (95% CI 0.78-0.87; I2 = 81.8%), whereas the pooled specificity was 0.75 (95% CI 0.66-0.82; I2 = 94.2%) and negative likelihood ratio was 0.23 (0.18-0.29). CONCLUSIONS Overall, RV dysfunction can be detected by CT imaging but the diagnostic accuracy when compared with echocardiography varies depending on specific findings. The presence of septal bowing appears to be highly specific for RV dysfunction. Our findings suggest that multiple CT findings of RV dysfunction may improve diagnostic accuracy and further studies are warranted.

Introduction There is an increased risk of stroke in patients with cancer–this risk is particularly heightened around the time of cancer diagnosis, although no studies have systematically quantified this risk in the literature. Patients newly diagnosed with cancer without prior stroke represent a highly susceptible population in whom there is a window of opportunity to study and implement primary prevention strategies. Therefore, the objective of this systematic review and meta-analysis is to identify the cumulative incidence of ischemic and hemorrhagic strokes during the first year after a diagnosis of cancer. Methods and analysis MEDLINE, EMBASE, and PubMed will be searched with the assistance from a medical information specialist, from 1980 until present. Eligible studies will include observational studies that have enrolled adult patients newly diagnosed with cancer and report outcomes of stroke during the first year of cancer diagnosis. We will exclude all randomized and non-randomized interventional studies. Data on participant characteristics, study design, baseline characteristics, and outcome characteristics will be extracted. Study quality will be assessed using the Newcastle-Ottawa Scale for cohort studies, and heterogeneity will be assessed using the I2 statistic. Pooled cumulative incidence will be calculated for ischemic and hemorrhagic strokes separately using a random-effects model. Ethics and dissemination No formal research ethics approval is necessary as primary data collection will not be done. We will disseminate our findings through scientific conference presentations, peer-reviewed publications, and social media/the press. The findings from this review will inform clinicians and patients regarding the risk of stroke in patients newly diagnosed with cancer by quantifying the cumulative incidence of each subtype of stroke during the first year after a diagnosis of cancer. This represents a window of opportunity to implement prevention strategies in a susceptible population. Registration ID with Open Science Framework osf.io/ucwy9.

Background Lack of data on balancing bleeding and thrombosis risk causes uncertainty about restarting anticoagulants after major bleeding. Anticoagulant reversal trials offer prospectively gathered data after major bleeding with well-documented safety events and restarting behavior. Objectives To examine the relationship of restarting anticoagulation with thrombosis, rebleeding, and death. Methods This is a posthoc analysis of a prospective factor Xa inhibitor reversal study at 63 centers in North America and Europe. We compared outcomes of restarted patients with those not restarted using landmark and time-dependent Cox proportional hazards models. Outcomes included thrombotic and bleeding events and death and a composite of all three. Results Of 352 patients enrolled, oral anticoagulation was restarted in 100 (28%) during 30-day follow-up. Thirty-four (9.7%) had thrombotic events, 15 (4.3%) had bleeding events (after day 3), and 49 (14%) died. In the landmark analysis comparing patients restarted within 14 days to those not, restarting was associated with decreased thrombotic events (hazard ratio [HR] = 0.112; 95% confidence interval [CI]: 0.001–0.944; p = 0.043) and increased rebleeding (HR = 8.39; 95% CI: 1.13–62.29; p = 0.037). The time-dependent Cox model showed evidence for a reduction in a composite (thrombotic events, bleeding, and death) attempting to capture net benefit (HR = 0.384; 95% CI: 0.161–0.915; p = 0.031). Conclusion This analysis provides modest evidence that restarting anticoagulation in factor Xa inhibitor-associated major bleeding patients is correlated with reduced risk of thrombotic events and increased risk of rebleeding. There is low-level evidence of net benefit for restarting. A randomized trial of restarting would be appropriate.

Background: Coronavirus disease 2019 (COVID-19)–related critical illness and acute illness are associated with a risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis for patients with COVID-19–related critical illness and acute illness who do not have confirmed or suspected VTE. Methods: ASH formed a multidisciplinary guideline panel and applied strict management strategies to minimize potential bias from conflicts of interest. The panel included 3 patient representatives. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic evidence reviews (up to 19 August 2020). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 2 recommendations. The panel issued conditional recommendations in favor of prophylactic-intensity anticoagulation over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19–related critical illness or acute illness who do not have confirmed or suspected VTE. Conclusions: These recommendations were based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials comparing different intensities of anticoagulation. They will be updated using a living recommendation approach as new evidence becomes available., Visual Abstract