Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.

BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.

BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Safety of outpatient management of cancer-associated pulmonary embolism: a retrospective study.

Not available.

Updates in the Incidence, Pathogenesis, and Management of Cancer and Venous Thromboembolism.

Patients with cancer are at higher risk of developing venous thromboembolism (VTE) compared with the general population. This elevated risk is due to several risk factors and multiple, overlapping thrombotic and hemostatic pathophysiological pathways that are specific to this patient population. Hence, the management of cancer-associated VTE can be challenging for clinicians. Patients with cancer-associated VTE are at higher risk of both recurrent events despite anticoagulation and bleeding complications due to the anticoagulant regimens. Direct oral anticoagulants have recently been shown to be effective, safe, and more convenient than parenteral low-molecular-weight heparin for the management of cancer-associated VTE. Despite these recent advances in anticoagulant therapy, many unmet needs remain in these patients (increased risk of bleeding with specific cancer types, drug-drug interactions, liver dysfunction). Factor XI inhibitors are currently being assessed for the management of cancer-associated VTE and may help clinicians address these important knowledge gaps.

Provision and evaluation of explanations within an automated planning-based approach to solving the multimorbidity problem.

The multimorbidity problem involves the identification and mitigation of adverse interactions that occur when multiple computer interpretable guidelines are applied concurrently to develop a treatment plan for a patient diagnosed with multiple diseases. Solving this problem requires decision support approaches which are difficult to comprehend for physicians. As such, the rationale for treatment plans generated by these approaches needs to be provided. OBJECTIVE: To develop an explainability component for an automated planning-based approach to the multimorbidity problem, and to assess the fidelity and interpretability of generated explanations using a clinical case study. METHODS: The explainability component leverages the task-network model for representing computer interpretable guidelines. It generates post-hoc explanations composed of three aspects that answer why specific clinical actions are in a treatment plan, why specific revisions were applied, and how factors like medication cost, patient's adherence, etc. influence the selection of specific actions. The explainability component is implemented as part of MitPlan, where we revised our planning-based approach to support explainability. We developed an evaluation instrument based on the system causability scale and other vetted surveys to evaluate the fidelity and interpretability of its explanations using a two dimensional comparison study design. RESULTS: The explainability component was implemented for MitPlan and tested in the context of a clinical case study. The fidelity and interpretability of the generated explanations were assessed using a physician-focused evaluation study involving 21 participants from two different specialties and two levels of experience. Results show that explanations provided by the explainability component in MitPlan are of acceptable fidelity and interpretability, and that the clinical justification of the actions in a treatment plan is important to physicians. CONCLUSION: We created an explainability component that enriches an automated planning-based approach to solving the multimorbidity problem with meaningful explanations for actions in a treatment plan. This component relies on the task-network model to represent computer interpretable guidelines and as such can be ported to other approaches that also use the task-network model representation. Our evaluation study demonstrated that explanations that support a physician's understanding of the clinical reasons for the actions in a treatment plan are useful and important.

Incidence and predictors of post-thrombotic syndrome in patients with proximal DVT in a real-world setting: findings from the GARFIELD-VTE registry.

Although substantial progress has been made in the pathophysiology and management of the post-thrombotic syndrome (PTS), several aspects still need clarification. Among them, the incidence and severity of PTS in the real world, the risk factors for its development, the value of patient's self-evaluation, and the ability to identify patients at risk for severe PTS. Eligible participants (n = 1107) with proximal deep-vein thrombosis (DVT) from the global GARFIELD-VTE registry underwent conventional physician's evaluation for PTS 36 months after diagnosis of their DVT using the Villalta score. In addition, 856 patients completed a Villalta questionnaire at 24 months. Variable selection was performed using stepwise algorithm, and predictors of severe PTS were incorporated into a multivariable risk model. The optimistic adjusted c-index was calculated using bootstrapping techniques. Over 36-months, 27.8% of patients developed incident PTS (mild in 18.7%, moderate in 5.7%, severe in 3.4%). Patients with incident PTS were older, had a lower prevalence of transient risk factors of DVT and a higher prevalence of persistent risk factors of DVT. Self-assessment of overall PTS at 24 months showed an agreement of 63.4% with respect to physician's evaluations at 36 months. The severe PTS multivariable model provided an optimistic adjusted c-index of 0.68 (95% CI 0.59-0.77). Approximately a quarter of DVT patients experienced PTS over 36 months after VTE diagnosis. Patient's self-assessment after 24 months provided added value for estimating incident PTS over 36 months. Multivariable risk analysis allowed good discrimination for severe PTS.

Comparison of rivaroxaban and low molecular weight heparin in the treatment of cancer-associated venous thromboembolism: a Swedish national population-based register study.

BACKGROUND: Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk. OBJECTIVES: To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT. METHODS: We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated. RESULTS: We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67). CONCLUSIONS: Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding. TRIAL REGISTRATION NUMBER: NCT05150938 (Registered 9 December 2021).

Occupational Risks of Radiation Exposure to Cardiologists.

PURPOSE OF REVIEW: Invasive cardiologists are exposed to large amounts of ionizing radiation. This review aims to summarize the main occupational risks in a radiation-exposed cardiology practice. RECENT FINDINGS: We carried out a literature review on the subject. The studies reviewed allowed us to list six main health risk categories possibly associated with radiation exposure among cardiologists: deoxyribonucleic acid (DNA) and biochemical damages; cancers; ocular manifestations; olfaction, vascular, and neuropsychological alterations; musculoskeletal problems; and reproductive risks. Our descriptive analysis demonstrates higher risks of DNA damage and lens opacities among radiation-exposed cardiology staff. Surveys and questionnaires have demonstrated a higher risk of musculoskeletal disease in exposed workers. Studies reported no difference in cancer frequency between radiation-exposed workers and controls. Changes in olfactory performance, neuropsychological aspects, and vascular changes have also been reported. Limited literature supports the security of continuing radiation-exposed work during pregnancy. Therefore, there is an urgent need to increase knowledge of the occupational risks of radiation exposure and to adopt technologies to reduce them.

Recurrent venous thromboembolism and bleeding with extended anticoagulation: the VTE-PREDICT risk score.

AIMS: Deciding to stop or continue anticoagulation for venous thromboembolism (VTE) after initial treatment is challenging, as individual risks of recurrence and bleeding are heterogeneous. The present study aimed to develop and externally validate models for predicting 5-year risks of recurrence and bleeding in patients with VTE without cancer who completed at least 3 months of initial treatment, which can be used to estimate individual absolute benefits and harms of extended anticoagulation. METHODS AND RESULTS: Competing risk-adjusted models were derived to predict recurrent VTE and clinically relevant bleeding (non-major and major) using 14 readily available patient characteristics. The models were derived from combined individual patient data from the Bleeding Risk Study, Hokusai-VTE, PREFER-VTE, RE-MEDY, and RE-SONATE (n = 15,141, 220 recurrences, 189 bleeding events). External validity was assessed in the Danish VTE cohort, EINSTEIN-CHOICE, GARFIELD-VTE, MEGA, and Tromsø studies (n = 59 257, 2283 recurrences, 3335 bleeding events). Absolute treatment effects were estimated by combining the models with hazard ratios from trials and meta-analyses. External validation in different settings showed agreement between predicted and observed risks up to 5 years, with C-statistics ranging from 0.48-0.71 (recurrence) and 0.61-0.68 (bleeding). In the Danish VTE cohort, 5-year risks ranged from 4% to 19% for recurrent VTE and 1% -19% for bleeding. CONCLUSION: The VTE-PREDICT risk score can be applied to estimate the effect of extended anticoagulant treatment for individual patients with VTE and to support shared decision-making.

Previous Ischemic Stroke Significantly Alters Stroke Risk in Newly Diagnosed Cancer Patients.

BACKGROUND: Previous ischemic stroke (IS) is a risk factor for subsequent IS in the general population; it is unclear if this relationship remains true in patients with cancer. Our objective was to examine the association between previous IS and risk for future IS in individuals newly diagnosed with cancer. METHODS: We conducted a retrospective population-based matched cohort study of newly diagnosed adult cancer patients (excluding nonmelanoma skin cancers and primary central nervous system tumors) in Ontario, Canada from 2010 to 2020; those with prior IS were matched (1:4) by age, sex, year of cancer diagnosis, cancer stage, and cancer site to those without a history of stroke. Cumulative incidence function curves were created to estimate the incidence of IS. Subdistribution adjusted hazard ratios (aHRs) and 95% CIs were calculated, where death was treated as a competing event. Multivariable analysis was adjusted for imbalanced baseline characteristics. RESULTS: We examined 65 525 individuals with cancer, including 13 070 with a history of IS. The median follow-up duration was 743 days (interquartile range, 177-1729 days). The incidence of IS following cancer diagnosis was 261.3/10 000 person-years in the cohort with prior IS and 75.3/10 000 person-years in those without prior IS. Individuals with prior IS had an increased risk for IS after cancer diagnosis compared with those without a history (aHR, 2.68 [95% CI, 2.41-2.98]); they also had more prevalent cardiovascular risk factors. The highest risk for stroke compared with those without a history of IS was observed in the gynecologic cancer (aHR, 3.84 [95% CI, 2.15-6.85]) and lung cancer (aHR, 3.18 [95% CI, 2.52-4.02]) subgroups. The risk of IS was inversely correlated with lag time of previous stroke; those with IS 1 year before their cancer diagnosis had the highest risk (aHR, 3.68 [95% CI, 3.22-4.22]). CONCLUSIONS: Among individuals with newly diagnosed cancer, those with IS history were almost 3× more likely to experience a stroke after cancer diagnosis, especially if the prediagnosis stroke occurred within 1 year preceding cancer diagnosis.

Efficacy and Safety of Anti-Xa-Guided Versus Fixed Dosing of Low Molecular Weight Heparin for Prevention of Venous Thromboembolism in Trauma Patients: A Systematic Review and Meta-Analysis.

PURPOSE: Trauma patients are at high risk of venous thromboembolism (VTE). We summarize the comparative efficacy and safety of anti-Xa-guided versus fixed dosing for low molecular weight heparin (LMWH) for the prevention of VTE in adult trauma patients. METHODS: We searched Medline and Embase from inception through June 1, 2022. We included randomized controlled trials or observational studies comparing anti-Xa-guided versus fixed dosing of LMWH for thromboprophylaxis in adult trauma patients. We incorporated primary data from 2 large observational cohorts. We pooled effect estimates using a random-effects model. We assessed risk of bias using the ROBINS-I tool for observational studies and assessed certainty of findings using GRADE methodology. RESULTS: We included 15 observational studies involving 10,348 patients. No randomized controlled trials were identified. determined that, compared to fixed LMWH dosing, anti-Xa-guided dosing may reduce deep vein thrombosis [adjusted odds ratio (aOR); 0.52, 95% CI: 0.40-0.69], pulmonary embolism (aOR: 0.48, 95% CI: 0.30-0.78) or any VTE (aOR: 0.54, 95% CI: 0.42-0.69), though all estimates are based on low certainty evidence. There was an uncertain effect on mortality (aOR: 1.06, 95% CI: 0.85-1.32) and bleeding events (aOR: 0.84, 95% CI: 0.50-1.39), limited by serious imprecision. We used several sensitivity and subgroup analyses to confirm the validity of our assumptions. CONCLUSION: Anti-Xa-guided dosing may be more effective than fixed dosing for prevention of deep vein thrombosis, pulmonary embolism, and VTE for adult trauma patients. These promising findings justify the need for a high-quality randomized study with the potential to deliver practice changing results.

Treatment of Cancer-Associated Thrombosis: Recent Advances, Unmet Needs, and Future Direction.

Cancer-associated thrombosis, with the incidence rising over the years, is associated with significant morbidity and mortality in patients with cancer. Recent advances in the treatment of cancer-associated venous thromboembolism (VTE) include the introduction of direct oral anticoagulants (DOACs), which provide a more convenient and effective option than low-molecular-weight heparin (LMWH). Nonetheless, important unmet needs remain including an increased risk of bleeding in certain patient subgroups such as those with gastroesophageal cancer, concerns about drug-drug interactions, and management of patients with severe renal impairment. Although DOACs are more convenient than LMWH, persistence can decline over time. Factor XI inhibitors have potential safety advantages over DOACs because factor XI appears to be essential for thrombosis but not hemostasis. In phase II trials, some factor XI inhibitors were superior to enoxaparin for the prevention of VTE after knee replacement surgery without increasing the risk of bleeding. Ongoing trials are assessing the efficacy and safety of factor XI inhibitors for the treatment of cancer-associated VTE.

Risk of venous thromboembolism or hemorrhage among individuals with chronic kidney disease on prophylactic anticoagulant after hip or knee arthroplasty.

Chronic kidney disease (CKD) confers a high risk of thrombosis and bleeding. However, little evidence exists regarding the optimal choice of postoperative thromboprophylaxis in these patients. We conducted a population-based, retrospective cohort study among adults ≥66 years old with CKD undergoing hip or knee arthroplasty who had filled an outpatient prophylactic anticoagulant prescription between 2010 and 2020 in Ontario, Canada. The primary outcomes of venous thrombosis (VTE) and hemorrhage were identified by validated algorithms using relevant diagnoses and billing codes. Overlap-weighted cause-specific Cox proportional hazard models were used to examine the association of direct oral anticoagulants (DOAC) on the 90-day risk of VTE and hemorrhage compared with low-molecular-weight heparin (LMWH). A total of 27 645 patients were prescribed DOAC (N = 22 943) or LMWH (N = 4702) after arthroplasty. Rivaroxaban was the predominant DOAC (94.5%), while LMWH mainly included enoxaparin (67%) and dalteparin (31.5%). DOAC users had higher eGFRs, fewer co-morbidities, and surgery in more recent years compared to LMWH users. After weighing, DOAC (compared with LMWH) was associated with a lower risk of VTE (DOAC: 1.5% vs. LMWH: 2.1%, weighted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59-0.94) and a higher risk of hemorrhage (DOAC: 1.3% vs. LMWH: 1.0%, weighted HR 1.44, 95% CI 1.04-1.99). Additional analyses including a more stringent VTE defining algorithm, different eGFR cut-offs, and limiting to rivaroxaban and enoxaparin showed consistent findings. Among elderly adults with CKD, DOAC was associated with a lower VTE risk and a higher hemorrhage risk compared to LMWH following hip or knee arthroplasty.

A community-of-practice-based evaluation methodology for knowledge intensive computational methods and its application to multimorbidity decision support.

OBJECTIVE: The study has dual objectives. Our first objective (1) is to develop a community-of-practice-based evaluation methodology for knowledge-intensive computational methods. We target a whitebox analysis of the computational methods to gain insight on their functional features and inner workings. In more detail, we aim to answer evaluation questions on (i) support offered by computational methods for functional features within the application domain; and (ii) in-depth characterizations of the underlying computational processes, models, data and knowledge of the computational methods. Our second objective (2) involves applying the evaluation methodology to answer questions (i) and (ii) for knowledge-intensive clinical decision support (CDS) methods, which operationalize clinical knowledge as computer interpretable guidelines (CIG); we focus on multimorbidity CIG-based clinical decision support (MGCDS) methods that target multimorbidity treatment plans. MATERIALS AND METHODS: Our methodology directly involves the research community of practice in (a) identifying functional features within the application domain; (b) defining exemplar case studies covering these features; and (c) solving the case studies using their developed computational methods-research groups detail their solutions and functional feature support in solution reports. Next, the study authors (d) perform a qualitative analysis of the solution reports, identifying and characterizing common themes (or dimensions) among the computational methods. This methodology is well suited to perform whitebox analysis, as it directly involves the respective developers in studying inner workings and feature support of computational methods. Moreover, the established evaluation parameters (e.g., features, case studies, themes) constitute a re-usable benchmark framework, which can be used to evaluate new computational methods as they are developed. We applied our community-of-practice-based evaluation methodology on MGCDS methods. RESULTS: Six research groups submitted comprehensive solution reports for the exemplar case studies. Solutions for two of these case studies were reported by all groups. We identified four evaluation dimensions: detection of adverse interactions, management strategy representation, implementation paradigms, and human-in-the-loop support. Based on our whitebox analysis, we present answers to the evaluation questions (i) and (ii) for MGCDS methods. DISCUSSION: The proposed evaluation methodology includes features of illuminative and comparison-based approaches; focusing on understanding rather than judging/scoring or identifying gaps in current methods. It involves answering evaluation questions with direct involvement of the research community of practice, who participate in setting up evaluation parameters and solving exemplar case studies. Our methodology was successfully applied to evaluate six MGCDS knowledge-intensive computational methods. We established that, while the evaluated methods provide a multifaceted set of solutions with different benefits and drawbacks, no single MGCDS method currently provides a comprehensive solution for MGCDS. CONCLUSION: We posit that our evaluation methodology, applied here to gain new insights into MGCDS, can be used to assess other types of knowledge-intensive computational methods and answer other types of evaluation questions. Our case studies can be accessed at our GitHub repository (https://github.com/william-vw/MGCDS).

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

BACKGROUND: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING: Eighteen sites between February 2011 and February 2021. PATIENTS: Patients with isolated subsegmental pulmonary embolism. INTERVENTION: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION: The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Safety of expedited-surgery protocols in anticoagulant-treated patients with hip fracture: a systematic review and meta-analysis.

BACKGROUND: Perioperative management of patients with hip fracture patients receiving oral anticoagulants requires navigating the risks associated with surgical delay and perioperative hemostasis. The aim of this systematic review and meta-analysis was to evaluate the effect of expedited-surgery protocols on time to surgery and perioperative outcomes in anticoagulant-treated patients with hip fracture. METHODS: We searched MEDLINE, Embase and CENTRAL from inception to May 5, 2020, to identify English-language studies reporting outcomes after expedited hip fracture surgery in patients receiving vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) before hospital admission. We performed a meta-analysis using Mantel-Haenszel weighting for dichotomous variables and inverse variance weighting for continuous variables. RESULTS: Among the 4253 citations identified, 14 studies were included. In the 6 studies eligible for meta-analysis, compared to hip fracture surgery before implementation of a VKA-reversal protocol, surgery after implementation of such a protocol was associated with a significant reduction in time to surgery (mean difference 45.31 h, 95% confidence interval [CI] 15.81 h to 74.80 h). Expedited surgery (within 48 h) in patients who received DOACs preoperatively was not associated with increased surgical duration (mean difference -7.29 min, 95% CI -22.5 min to 7.95 min) or 30-day mortality (odds ratio [OR] 1.30, 95% CI 0.49 to 3.89) compared to patients who did not receive anticoagulants (control patients). However, expedited surgery in DOAC-treated patients was associated with an increased blood transfusion risk compared to control patients (OR 0.58, 95% CI 0.36 to 0.96). CONCLUSION: Implementing a VKA-reversal protocol for patients with hip fracture is effective in decreasing time to surgery, without an increased bleeding risk. Performing hip fracture surgery within 48 hours in DOAC-treated patients is also safe, with a small increase in blood transfusion risk.

Efficacy and Safety of Low Molecular Weight Heparin Versus Unfractionated Heparin for Prevention of Venous Thromboembolism in Trauma Patients: A Systematic Review and Meta-analysis.

PURPOSE: Trauma patients are at high risk of VTE. We summarize the efficacy and safety of LMWH versus UFH for the prevention of VTE in trauma patients. METHODS: We searched 6 databases from inception through March 12, 2021. We included randomized controlled trials (RCTs) or observational studies comparing LMWH versus 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 Risk of Bias in Non-Randomized Studies (ROBINS)-I tool for observational studies and assessed certainty of findings using Grading of Recommendations, Assessment, Development and Evaluations 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 (RR 0.67, 95% 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 0.56 (95% CI 0.50 to 0.62)] and mortality (adjusted odds ratio 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)]. CONCLUSIONS: Among adult trauma patients, LMWH is superior to UFH for deep vein thrombosis and VTE prevention and may additionally reduce pulmonary embolism and mortality. The impact on adverse events and heparin induced thrombocytopenia is uncertain.

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.

BACKGROUND: Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS: Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).

Prognostic Factors Associated With Development of Venous Thromboembolism in Critically Ill Patients-A Systematic Review and Meta-Analysis.

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.

Direct oral anticoagulants and cancer-associated VTE: good for all, or just some?

Venous thromboembolism (VTE) is associated with significant mortality and morbidity in patients with cancer. Therefore, tailoring anticoagulation is of utmost importance to decrease the risk of recurrent VTE while minimizing the risk of bleeding. Direct oral anticoagulants have been recently compared with low-molecular-weight heparin for the management of acute cancer-associated thrombosis. Although direct oral anticoagulants are a welcome addition, clinicians need to incorporate clinical characteristics, drug-drug interactions, and patient preference in decision making.