ASH living guidelines on use of anticoagulation for thromboprophylaxis in patients with COVID-19: executive summary.

COVID-19-related critical and acute illness are associated with an increased risk of venous thromboembolism (VTE). These evidence-based recommendations of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other healthcare professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness, acute illness, and those being discharged from the hospital, who do not have suspected or confirmed VTE. ASH formed a multidisciplinary panel, including three patient representatives, and applied a conflicts of interest management policy to minimize potential bias. The Michael G. DeGroote Cochrane Canada and MacGRADE Centres at McMaster University supported the guideline development process, including performing systematic evidence reviews (up to June 2023). 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 certainty of the evidence and make recommendations, which were subject to public comment. This is an executive summary of three updated recommendations that have been published which concludes the living phase of the guidelines. For critically ill patients with COVID-19, the panel issued conditional recommendations in favor of (a) prophylactic-intensity over therapeutic-intensity anticoagulation and (b) prophylactic-intensity over intermediate-intensity anticoagulation. For acutely ill patients with COVID-19, conditional recommendations were made in favor of (a) prophylactic-intensity over intermediate-intensity anticoagulation and (b) therapeutic-intensity over prophylactic-intensity anticoagulation. The panel also issued a conditional recommendation against the use of post-discharge extended pharmacologic thromboprophylaxis. These three conditional recommendations were made based on low or very low certainty in the evidence, underscoring the need for additional, high-quality randomized controlled trials in patients with COVID-19-related illness.

Anticoagulation for the Prevention of Arterial Thromboembolism in Cancer Patients by Primary Tumor Site: A Systematic Review and Meta-Analysis of Randomized Trials.

AIMS: Incidence of arterial thromboembolism (ATE) among ambulatory cancer patients varies by primary tumor site. However, it is unclear whether this alters the benefit-to-harm profile of prophylactic anticoagulation for ATE prevention. Therefore, we systematically evaluated the efficacy and safety of anticoagulants for ATE prevention among ambulatory cancer patients according to the primary tumor site. METHODS AND RESULTS: We conducted a systematic review using Medline, Embase, SCOPUS, and CENTRAL, and included randomized trials comparing prophylactic anticoagulation to no anticoagulation among ambulatory cancer patients who initiated tumor-directed systemic therapy. Incidence of symptomatic ATE (acute ischemic stroke, acute myocardial infarction or peripheral artery occlusion) and major bleeding, as well as risk differences (RDs) attributable to anticoagulation were meta-analyzed by primary tumor site using random-effects modeling. We included 10 randomized controlled trials with 9,875 patients with follow-up ranging from 3.3 to 68 (median 6.6) months. While prophylactic anticoagulation did not reduce ATE risks overall (RD -0.49%; 95% CI -0.49% to 0.01%; I2=0%), it conferred a protective effect among pancreatic cancer patients (RD -3.2%; 95%CI -5.7% to -0.8%; I2=0%) without a detectable increase in major bleeding (RD -1.4%; 95% CI -4.6% to 1.8%; I2=0%). Prophylactic anticoagulation was not associated with ATE risk reduction in other tumor sites. CONCLUSION: Based on available evidence, prophylactic anticoagulation did not reduce ATE risk among ambulatory cancer patients overall. However, we observed lower incidence of ATE among pancreatic cancer patients randomized to receive anticoagulation. Prophylactic anticoagulant use to reduce ATEs in pancreatic cancer should be evaluated in future research.

Oral Anticoagulant Use and Post-Fall Mortality in Long-Term Care Home Residents.

OBJECTIVES: Long-term care (LTC) residents are susceptible to falling and the risk of subsequent morbidity and mortality may be compounded with concurrent anticoagulation use. Uncertainty exists around the benefit and harm of anticoagulation use for residents with a high risk for falls because of concerns of major bleeding complications. We aimed to examine if anticoagulant use increases mortality risk among LTC residents who fall. DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Older adults (≥65 years) admitted to a LTC facility in Ontario, Canada between January 1, 2010, and December 1, 2019, who were transferred to emergency departments for fall-related injuries. METHODS: The exposure was the use of an oral anticoagulant (OAC). The primary outcome was mortality within 30 days of transfer. Secondary outcomes were major hemorrhage and care utilization. We used hierarchical logistic regression models to examine the association between the use of OAC and 30-day mortality. RESULTS: There were 56,419 residents transferred to the hospital for a fall, of whom 9611 (17.0%) were on an OAC. At 30 days, 5794 (10.3%) of the cohort had died: 12.0% (1151) on an OAC and 9.90% (4643) not on an OAC [risk difference (RD), 2.1%; 95% CI, 1.40%-2.82%]. There were 485 major hemorrhage cases: 1.3% (125) on an OAC and 0.8% (360) not on an OAC (RD, 0.5%; 95% CI, 0.26%-0.74%). Multivariable analysis found no significant association between OAC use and 30-day mortality [odds ratio (OR), 0.98; 95% CI, 0.90-1.06], but an increased risk of major hemorrhage (OR, 1.31; 95% CI, 1.04-1.66). Both groups had similar health system and neurosurgical care utilization. CONCLUSIONS AND IMPLICATIONS: Among LTC residents transferred to the emergency department for fall-related injuries, OACs did not increase the risk of post-fall mortality. OAC prescribing for frail older adults who experience falls should consider their individual risk profile.

Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: guidance from the SSC of the ISTH.

While advanced liver disease was previously considered to be an acquired bleeding disorder, there is increasing recognition of an associated prothrombotic state with patients being at higher risk of atrial fibrillation (AF) and stroke and venous thromboembolism (VTE) including portal vein thrombosis (PVT). We review the available literature on epidemiology, pathophysiology, and risk factors and provide guidance on anticoagulant management of these conditions in adults with cirrhosis. In patients with Child-Pugh A or B cirrhosis and AF, we recommend anticoagulation with standard-dose direct oral anticoagulants (DOACs) in accordance with cardiology guideline recommendations for patients without liver disease. In those with Child-Pugh C cirrhosis, there is inadequate evidence with respect to the benefit and risk of anticoagulation for stroke prevention in AF. In patients with cirrhosis and acute deep vein thrombosis or pulmonary embolism, we recommend anticoagulation and suggest use of either a DOAC or low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) in Child-Pugh A or B cirrhosis and LMWH alone (or as a bridge to VKA in patients with a normal baseline international normalized ratio) in Child-Pugh C cirrhosis. We recommend anticoagulation for patients with cirrhosis and symptomatic PVT. We suggest anticoagulation for those with asymptomatic, progressing PVT and recommend continuing extended anticoagulation for liver transplant candidates with PVT.

Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease.

Balancing the safety and efficacy of antithrombotic agents in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs and for an increased risk of bleeding. In this Review, we address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities. For those with gastrointestinal bleeding (GIB), we summarize a general scheme for risk stratification and clinical evidence on risk reduction approaches, such as limiting the use of concomitant medications that increase the risk of GIB and the potential utility of gastrointestinal protection strategies (such as proton pump inhibitors or histamine type 2 receptor antagonists). Furthermore, we summarize the best available evidence and potential gaps in our knowledge on tailoring antithrombotic therapy in patients with active or recent GIB and in those at high risk of GIB but without active or recent GIB. Finally, we review the recommendations provided by major medical societies, highlighting the crucial role of teamwork and multidisciplinary discussions to customize the antithrombotic regimen in patients with coexisting cardiovascular and gastrointestinal diseases.

Prognostic factors associated with venous thromboembolism following traumatic injury: A systematic review and meta-analysis.

INTRODUCTION: Trauma patients are at increased risk of venous thromboembolism (VTE), including deep venous thrombosis and/or pulmonary embolism. We conducted a systematic review and meta-analysis summarizing the association between prognostic factors and the occurrence of VTE following traumatic injury. METHODS: We searched the Embase and Medline databases from inception to August 2023. We identified studies reporting confounding adjusted associations between patient, injury, or postinjury care factors and risk of VTE. We performed meta-analyses of odds ratios using the random-effects method and assessed individual study risk of bias using the Quality in Prognosis Studies tool. RESULTS: We included 31 studies involving 1,981,946 patients. Studies were predominantly observational cohorts from North America. Factors with moderate or higher certainty of association with increased risk of VTE include older age, obesity, male sex, higher Injury Severity Score, pelvic injury, lower extremity injury, spinal injury, delayed VTE prophylaxis, need for surgery, and tranexamic acid use. After accounting for other important contributing prognostic variables, a delay in the delivery of appropriate pharmacologic prophylaxis for as little as 24 to 48 hours independently confers a clinically meaningful twofold increase in incidence of VTE. CONCLUSION: These findings highlight the contribution of patient predisposition, the importance of injury pattern, and the impact of potentially modifiable postinjury care on risk of VTE after traumatic injury. These factors should be incorporated into a risk stratification framework to individualize VTE risk assessment and support clinical and academic efforts to reduce thromboembolic events among trauma patients. LEVEL OF EVIDENCE: Systematic Review and Meta-Analysis; Level III.

When Direct Oral Anticoagulants Should Not Be Standard Treatment: JACC State-of-the-Art Review.

For most patients, direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prevention in atrial fibrillation and for venous thromboembolism treatment. However, randomized controlled trials suggest that DOACs may not be as efficacious or as safe as the current standard of care in conditions such as mechanical heart valves, thrombotic antiphospholipid syndrome, and atrial fibrillation associated with rheumatic heart disease. DOACs do not provide a net benefit in conditions such as embolic stroke of undetermined source. Their efficacy is uncertain for conditions such as left ventricular thrombus, catheter-associated deep vein thrombosis, cerebral venous sinus thrombosis, and for patients with atrial fibrillation or venous thrombosis who have end-stage renal disease. This paper provides an evidence-based review of randomized controlled trials on DOACs, detailing when they have demonstrated efficacy and safety, when DOACs should not be the standard of care, where their safety and efficacy are uncertain, and areas requiring further research.

Country and health expenditure are major predictors of withholding anticoagulation in atrial fibrillation patients at high risk of stroke.

BACKGROUND: Guidelines for patients with atrial fibrillation (AF) at high thromboembolic risk recommend oral anticoagulants (OACs) for preventing stroke and systemic embolism (SE). The reasons for guideline non-adherence are still unclear. AIM: The aim is to identify clinical, demographic and non-patient characteristics associated with withholding OAC in patients with AF at high stroke risk. METHODS: Patients in the Global Anticoagulant Registry in the FIELD-AF, newly diagnosed with AF between March 2010 and August 2016, and with CHA2DS2-VASc Score≥2 (excluding sex), were grouped by OAC treatment at enrolment. Factors associated with OAC non-use were analysed by multivariable logistic regression. RESULTS: Of 40 416 eligible patients, 12 126 (30.0%) did not receive OACs at baseline. Globally, OAC prescription increased over time, from 60.4% in 2010-2011 to 74.7% in 2015-2016. Country of enrolment was the major predictor for OAC withholding (χ2-df=2576). Clinical predictors of OAC non-use included type of AF (χ2-df=404), history of bleeding (χ2-df=263) and vascular disease (χ2-df=99). OACs were used most frequently around the age of 75 years and decreasingly with younger as well as older age beyond 75 years (χ2-df=148). Non-cardiologists (χ2-df=201) and emergency room physicians (χ2-df=14) were less likely to prescribe OACs. OAC prescription correlated positively with country health expenditure. CONCLUSIONS: Approximately one out of three AF patients did not receive OAC, while eligible according to the guidelines. Country of enrolment was the major determinant of anticoagulation strategy, while higher country health expenditure was associated with lower likelihood of withholding anticoagulation.

Small-Volume Blood Collection Tubes to Reduce Transfusions in Intensive Care: The STRATUS Randomized Clinical Trial.

Importance: Blood collection for laboratory testing in intensive care unit (ICU) patients is a modifiable contributor to anemia and red blood cell (RBC) transfusion. Most blood withdrawn is not required for analysis and is discarded. Objective: To determine whether transitioning from standard-volume to small-volume vacuum tubes for blood collection in ICUs reduces RBC transfusion without compromising laboratory testing procedures. Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 25 adult medical-surgical ICUs in Canada (February 5, 2019 to January 21, 2021). Interventions: ICUs were randomized to transition from standard-volume (n = 10 940) to small-volume tubes (n = 10 261) for laboratory testing. Main Outcomes and Measures: The primary outcome was RBC transfusion (units per patient per ICU stay). Secondary outcomes were patients receiving at least 1 RBC transfusion, hemoglobin decrease during ICU stay (adjusted for RBC transfusion), specimens with insufficient volume for testing, length of stay in the ICU and hospital, and mortality in the ICU and hospital. The primary analysis included patients admitted for 48 hours or more, excluding those admitted during a 5.5-month COVID-19-related trial hiatus. Results: In the primary analysis of 21 201 patients (mean age, 63.5 years; 39.9% female), which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference in RBC units per patient per ICU stay (relative risk [RR], 0.91 [95% CI, 0.79 to 1.05]; P = .19; absolute reduction of 7.24 RBC units/100 patients per ICU stay [95% CI, -3.28 to 19.44]). In a prespecified secondary analysis (n = 27 411 patients), RBC units per patient per ICU stay decreased after transition from standard-volume to small-volume tubes (RR, 0.88 [95% CI, 0.77 to 1.00]; P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay [95% CI, 0.24 to 20.76]). Median decrease in transfusion-adjusted hemoglobin was not statistically different in the primary population (mean difference, 0.10 g/dL [95% CI, -0.04 to 0.23]) and lower in the secondary population (mean difference, 0.17 g/dL [95% CI, 0.05 to 0.29]). Specimens with insufficient quantity for analysis were rare (≤0.03%) before and after transition. Conclusions and Relevance: Use of small-volume blood collection tubes in the ICU may decrease RBC transfusions without affecting laboratory analysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03578419.

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.

Small-volume tubes to reduce anemia and transfusion (STRATUS): a pilot study.

PURPOSE: Blood sampling for diagnostic testing causes blood loss. Small-volume tubes have the same cost, dimensions, and blood-draw techniques as standard-volume tubes, and are compatible with laboratory equipment; however, they are not commonly used. We sought to assess the feasibility of a stepped-wedge cluster trial to determine whether small-volume tubes reduce transfusion compared with standard-volume tubes in intensive care unit (ICU) patients. METHODS: We conducted a prospective mixed-methods pilot study (before-after design) in one ICU with a six-week control period (standard-volume tubes) and a six-week intervention period (small-volume tubes). All patients admitted to the ICU were included. Feasibility was assessed as successful switch to small-volume tubes; adherence to tube size; sufficient volume for testing; user acceptance; barriers and facilitators to implementation; and 95% transfusion collection. We explored end-user acceptability using focus groups. RESULTS: One hundred and sixty-five patients were included in the standard-volume and 204 in the small-volume periods. Transition to small-volume tubes was successful. Random audits showed 100% compliance. The proportion of samples with inadequate volume for testing was the same for both groups (both, 0.2%). Based on ten focus groups, small-volume tubes were acceptable with no barriers identified. Transfusion data collection was 100%. Median [interquartile range] estimated blood loss due to laboratory testing per patient per day in ICU was 11 [8-17] mL with standard-volume and 6 [4-8] mL with small-volume tubes. CONCLUSION: Small-volume tubes can be implemented with acceptability to end-users and without barriers. They did not result in an increased frequency of inadequate samples. These results inform a trial to determine whether small-volume tubes reduce transfusion. STUDY REGISTRATION: ClinicalTrials.gov (NCT03284944); registered 15 September 2017.

RéSUMé: OBJECTIF: Les prélèvements sanguins pour les tests diagnostiques provoquent des pertes de sang. Les tubes de prélèvement de petit volume entraînent le même coût, ont les mêmes dimensions et nécessitent les mêmes techniques de prélèvement sanguin que les tubes de volume standard, en plus d'être compatibles avec l'équipement de laboratoire; cependant, ils ne sont pas couramment utilisés. Nous avons cherché à évaluer la faisabilité d'un essai clinique à intervention échelonnée visant à déterminer si les tubes de petit volume réduisaient la transfusion par rapport aux tubes de volume standard chez les patient·es de l'unité de soins intensifs (USI). MéTHODE: Nous avons mené une étude pilote prospective à méthodes mixtes (conception avant-après) dans une unité de soins intensifs, avec une période de contrôle de six semaines (tubes de volume standard) et une période d'intervention de six semaines (tubes de petit volume). Tou·tes les patient·es admis·es à l'USI ont été inclus·es. La faisabilité a été évaluée comme étant la transition réussie vers des tubes de petit volume; le respect de la taille du tube; un volume suffisant pour les tests sanguins; l'acceptation de l'utilisateur·trice; les obstacles et les facilitateurs à la mise en œuvre; et une collecte de données de transfusion de 95 %. Nous avons exploré l'acceptabilité par l'utilisateur·trice final·e à l'aide de groupes de discussion. RéSULTATS: Cent soixante-cinq patient·es ont été inclus·es dans le groupe volume standard et 204 dans les groupes pour la période de petit volume. La transition vers des tubes de petit volume a été couronnée de succès. Les audits aléatoires ont montré une observance de 100 %. La proportion d'échantillons dont le volume était insuffisant pour l'analyse était la même dans les deux groupes (0,2 % dans les deux cas). D'après dix groupes de discussion, les tubes de faible volume étaient acceptables et aucun obstacle n'a été identifié. La collecte de données transfusionnelles était de 100 %. Les pertes de sang médianes estimées [écart interquartile] dues aux tests de laboratoire par patient·e et par jour à l'USI étaient de 11 [8 à 17] mL avec un volume standard et de 6 [4 à 8] mL avec des tubes de petit volume. CONCLUSION: Les tubes de petit volume peuvent être mis en œuvre en étant acceptés par les utilisateur·trices et sans obstacles. Ils n'ont pas entraîné une augmentation de la fréquence des échantillons inadéquats. Ces résultats procurent des informations pour une étude visant à déterminer si les tubes de petit volume réduisent la transfusion. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT03284944); enregistré le 15 septembre 2017.

Effect of PCC on Thrombin Generation among Patients on Factor Xa Inhibitors with Major Bleeding or Needing Urgent Surgery (GAUGE): Design and Rationale.

Background Direct factor Xa inhibitors (FXaIs) account for most oral anticoagulant use and FXaI-associated bleeding events are common. Clinicians have variable national and regional access to specific FXaI reversal agents such as andexanet alfa. Many centers have adopted the use of prothrombin complex concentrates (PCCs) as hemostatic therapy for FXaI-associated major bleeding events. PCC does not impact circulating FXaI levels and its mechanism of action to achieve hemostasis in FXaI-associated bleeding is uncertain. While PCC increases quantitative thrombin generation assay (TGA) parameters, it does not correct FXaI-altered thrombin generation kinetics, nor does it normalize thrombin generation. Clinical data supporting the use of PCC are based on cohort studies reporting clinical hemostatic efficacy, which is difficult to measure. The benefits of PCC for FXaI-associated bleeding beyond supportive care are uncertain. Objective GAUGE is a prospective observational study designed to measure the effects of four-factor PCC administration (Octaplex) on TGA parameters among patients with FXaI-associated bleeding or needing urgent surgery. Methods Laboratory outcomes will include the mean paired change in TGA parameters from pre- to post-PCC administration and the proportion of participants whose post-PCC TGA values fall within a defined reference range. Clinical outcomes will include hemostatic efficacy, thromboembolic complications, and all-cause death at 30 days post-PCC. Conclusion Development of a viable and universally accessible FXaI bleed management strategy is crucial. GAUGE will provide in vivo data on the effects of PCC among patients with FXaI-associated bleeding.

A scoping review protocol on diagnostic strategies to detect occult malignancies in individuals with ischemic stroke.

BACKGROUND: Emerging data show an increased risk of ischemic stroke in patients with a new diagnosis of cancer. As the risk of stroke begins to increase 150 days before cancer is diagnosed, stroke may be the first clinical manifestation of undiagnosed cancer. About 6% of patients with cryptogenic ischemic stroke (unknown etiology after diagnostic evaluations) are diagnosed with cancer within one year. However, the optimal cancer screening strategy in this population is not known. We aim to conduct a scoping review of screening strategies for occult cancer in individuals with ischemic stroke. METHODS: Electronic databases including MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCOhost) and Scopus will be systematically searched to identify articles that report on screening strategies for occult cancer in individuals with ischemic stroke. At least two investigators will independently perform two-stage study selection consisting of title/abstract screening and full-text review, followed by data extraction. Thereafter, a thematic analysis will be conducted to provide an overview of what diagnostic tests/strategies have been used, and their clinical utility in terms of positive and negative predictive value (when available). CONCLUSION: We anticipate that the findings of this scoping review will identify strategies used to detect occult cancer in individuals with ischemic stroke and summarize their clinical utility (if reported). Addressing this knowledge gap will help guide the development of future clinical trials on occult cancer screening patients with ischemic stroke.

Definitions of fatal bleeding in clinical studies evaluating anticoagulant treatment for venous thromboembolism: A scoping review.

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.

Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization.

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.

Role of statins in the prevention of post-thrombotic syndrome after a deep vein thrombosis event: a systematic review and meta-analysis.

BACKGROUND: Post-thrombotic syndrome (PTS) is the most frequent long-term complication of deep vein thrombosis. Apart from anticoagulation, there are no medications, procedures, devices, or lifestyle changes that effectively prevent PTS. There is a growing interest in the potential protective effects of statins for the prevention of PTS. OBJECTIVE: To conduct a systematic review and meta-analysis on the role of statins to prevent PTS after a DVT event. METHODS: We searched the MEDLINE(R) ALL, Embase, Cochrane Central Register of Controlled Trials, and Scopus from inception to April 5, 2022. The main concepts searched were "statins" and "post thrombotic syndrome." There was no language restriction. The main outcome measure was the incidence rate ratio (IRR) for PTS associated with exposure to statins. RESULTS: Of 1971 screened records, 5 studies were included in the meta-analysis (2 retrospective cohorts and 3 randomized controlled trials [RCTs]). The pooled incidence of PTS was 34.8% per patient-year (95% CI, 9.5-127.4) in patients receiving a statin and 41.6% per patient-year (95% CI, 13.2-132) in controls. Exposure to statins was associated with a significantly decreased risk of PTS (IRR, 0.78; 95% CI, 0.63-0.96, I2 = 0%). Meta-analysis of the 2 retrospective cohorts found a significant reduction in the risk of developing PTS (IRR, 0.68; 95% CI, 0.51-0.91), whereas meta-analysis of RCTs showed no reduction in PTS occurrence (IRR, 0.92; 95% CI, 0.68-1.25). CONCLUSIONS: Although this systematic review suggests that statins may reduce PTS incidence by 22% after deep vein thrombosis, meta-analysis of RCTs showed no risk reduction. Confirmation of the efficacy of statins on the prevention of PTS should be assessed in larger RCTs.