International Medical Prevention Registry Research Articles

Risk Assessment Models for Venous Thromboembolism in Medical Inpatients

Thromboprophylaxis is recommended for medical inpatients at risk of venous thromboembolism (VTE). Risk assessment models (RAMs) have been developed to stratify VTE risk, but a prospective head-to-head comparison of validated RAMs is lacking. To prospectively validate an easy-to-use RAM, the simplified Geneva score, and compare its prognostic performance with previously validated RAMs. This prospective cohort study was conducted from June 18, 2020, to January 4, 2022, with a 90-day follow-up. A total of 4205 consecutive adults admitted to the general internal medicine departments of 3 Swiss university hospitals for hospitalization for more than 24 hours due to acute illness were screened for eligibility; 1352 without therapeutic anticoagulation were included. At admission, items of 4 RAMs (ie, the simplified and original Geneva score, the Padua score, and the IMPROVE [International Medical Prevention Registry on Venous Thromboembolism] score) were collected. Patients were stratified into high and low VTE risk groups according to each RAM. Symptomatic VTE within 90 days. Of 1352 medical inpatients (median age, 67 years [IQR, 54-77 years]; 762 men [55.4%]), 28 (2.1%) experienced VTE. Based on the simplified Geneva score, 854 patients (63.2%) were classified as high risk, with a 90-day VTE risk of 2.6% (n = 22; 95% CI, 1.7%-3.9%), and 498 patients (36.8%) were classified as low risk, with a 90-day VTE risk of 1.2% (n = 6; 95% CI, 0.6%-2.6%). Sensitivity of the simplified Geneva score was 78.6% (95% CI, 60.5%-89.8%) and specificity was 37.2% (95% CI, 34.6%-39.8%); the positive likelihood ratio of the simplified Geneva score was 1.25 (95% CI, 1.03-1.52) and the negative likelihood ratio was 0.58 (95% CI, 0.28-1.18). In head-to-head comparisons, sensitivity was highest for the original Geneva score (82.1%; 95% CI, 64.4%-92.1%), while specificity was highest for the IMPROVE score (70.4%; 95% CI, 67.9%-72.8%). After adjusting the VTE risk for thromboprophylaxis use and site, there was no significant difference between the high-risk and low-risk groups based on the simplified Geneva score (subhazard ratio, 2.04 [95% CI, 0.83-5.05]; P = .12) and other RAMs. Discriminative performance was poor for all RAMs, with an area under the receiver operating characteristic curve ranging from 53.8% (95% CI, 51.1%-56.5%) for the original Geneva score to 58.1% (95% CI, 55.4%-60.7%) for the simplified Geneva score. This head-to-head comparison of validated RAMs found suboptimal accuracy and prognostic performance of the simplified Geneva score and other RAMs to predict hospital-acquired VTE in medical inpatients. Clinical usefulness of existing RAMs is questionable, highlighting the need for more accurate VTE prediction strategies.

Converting IMPROVE bleeding and VTE risk assessment models into a fast-and-frugal decision tree for optimal VTE prophylaxis

AbstractCurrent hospital venous thromboembolism (VTE) prophylaxis for medical patients is characterized by both underuse and overuse. The American Society of Hematology (ASH) has endorsed the use of risk assessment models (RAM) as an approach to individualize VTE prophylaxis by balancing overuse (excessive risk of bleeding) and underuse (risk of avoidable VTE). ASH has endorsed IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) risk assessment models; the only RAM to assess short-term bleeding and VTE risk in acutely ill medical inpatients. ASH, however, notes that no RAMs have been thoroughly analyzed for their effect on patient outcomes. We aimed to validate the IMPROVE models and adapt them into a simple, fast-and-frugal (FFT) decision tree to evaluate the impact of VTE prevention on health outcomes and costs. We used 3 methods: the “best evidence” from ASH guidelines, a “learning health system paradigm” combining guideline and real-world data from the Medical University of South Carolina (MUSC), and a “real-world data” approach based solely on MUSC data retrospectively extracted from electronic records. We found that the most effective VTE prevention strategy used the FFT decision tree, guided by an IMPROVE VTE score of ≥2 or ≥4 and a bleeding score of <7. This method could prevent 45% of unnecessary treatments, saving ∼$5 million annually for patients such as the MUSC cohort. We recommend integrating IMPROVE models into hospital electronic medical records as a point-of-care tool, thereby enhancing VTE prevention in hospitalized medical patients.

High-risk subgroups were not identified to benefit from thromboprophylaxis after hospitalization for COVID-19

BackgroundThe Accelerating COVID-19 Therapeutic Interventions and Vaccines-4c trial investigated prophylactic apixaban for 30 days following hospitalization for COVID-19. The overall incidence of early postdischarge death or thromboembolism was low, and the trial was closed early. ObjectivesTo identify a high-risk patient population who might benefit from postdischarge thromboprophylaxis through subgroup analyses stratified by age, race/ethnicity, obesity, D-dimer elevation, World Health Organization score, and modified International Medical Prevention Registry on Venous Thromboembolism score on 30-day composite outcome of all-cause death, arterial thromboembolism (ATE), and venous thromboembolism (VTE). MethodsCumulative incidences of all-cause death, ATE, and VTE within 30 days were described for each subgroup. Time to death, ATE, or VTE by 30 days was analyzed using Cox proportional hazard models with interaction testing for each subgroup. ResultsAmong 1217 patients randomized to apixaban or placebo group, 32% were >60 years old. Modified International Medical Prevention Registry on Venous Thromboembolism score was ≥4 in 2% and 2 or 3 with an elevated D-dimer in an additional 9% of participants. The overall incidence of the primary endpoint was 2.13% in the apixaban group and 2.31% in the placebo group. At day 30, similar rates of the primary endpoint occurred within subgroups, except for participants aged >60 years. No benefit of thromboprophylaxis was seen in any subgroup. ConclusionThe combined incidence of 30-day death, ATE, and VTE was low in patients who survived COVID-19 hospitalization, except in patients over age 60 years. Due to the limited number of events, the findings remain inconclusive; nonetheless, the study did not identify a high-risk subgroup that would derive benefits from extended thromboprophylaxis.

The Use of Risk Scores for Thromboprophylaxis in Medically Ill Patients-Rationale and Design of the RICO trial.

Background  Venous thromboembolism (VTE) in hospitalized medically ill patients is a significant cause of morbidity and mortality. Guidelines suggest that VTE and bleeding risk assessment models (RAMs) should be integrated into the clinical decision-making process on thromboprophylaxis. However, poor evidence is available comparing the use of a RAM versus clinical judgement in evaluating VTE and bleeding occurrence. Methods  Reducing Important Clinical Outcomes in hospitalized medical ill patients (RICO) is a multicenter, cluster-randomized, controlled clinical trial (ClinicalTrials.gov Identifier: NCT04267718). Acutely ill patients hospitalized in Internal Medicine wards are randomized to the use of RAMs-namely the Padua Prediction Score and the International Medical Prevention Registry on Venous Thromboembolism Bleeding Score-or to clinical judgement. The primary study outcome is a composite of symptomatic objectively confirmed VTE and major bleeding at 90-day follow-up. Secondary endpoints include the evaluation of clinical outcomes at hospital discharge and the assessment of VTE prophylaxis prescription during the study period. In order to demonstrate a 50% reduction in the primary outcome in the experimental group and assuming an incidence of the primary outcome of 3.5% in the control group at 90-day; 2,844 patients across 32 centers will be included in the study. Discussion  The RICO trial is a randomized study of clinical management assessing the role of RAMs in hospitalized medical ill patients with the aim of reducing VTE and bleeding occurrence. The study has the potential to improve clinical practice since VTE still represents an important cause of morbidity and mortality in this setting.

Association of pharmacologic thromboprophylaxis with clinically relevant bleeding and hospital-acquired anemia in medical inpatients: the risk stratification for hospital-acquired venous thromboembolism in medical patients study

BackgroundPharmacologic thromboprophylaxis (pTPX) might exacerbate the risk of clinically relevant bleeding (CRB) and hospital-acquired anemia (HAA) in older multimorbid inpatients. ObjectivesWe aimed to evaluate the association of pTPX use with CRB and HAA. MethodsWe used data from a prospective cohort study conducted in 3 Swiss university hospitals. Adult patients admitted to internal medicine wards with no therapeutic anticoagulation were included. pTPX use was ascertained during hospitalization. Outcomes were in-hospital CRB and HAA. We calculated incidence rates by status of pTPX. We assessed the association of pTPX with CRB using survival analysis and with HAA using logistic regression, adjusted for infection, length of stay, and the International Medical Prevention Registry on Venous Thromboembolism bleeding risk score. ResultsAmong 1305 patients (mean age, 63.7 years; 44% women, 90% at low risk of bleeding), 809 (62%) received pTPX. The incidence of CRB was 2.4 per 1000 patient-days and was not significantly higher in patients with pTPX than in those without. We found no significant association between pTPX and CRB. HAA was frequent (20.2%) and higher in patients with pTPX than in those without (23.2% vs 15.3%). The incidence of HAA was 21.2 per 1000 patient-days and did not significantly differ between patients with pTPX and those without. We found an association between pTPX and HAA (adjusted odds ratio, 1.4; 95% CI, 1.0-2.1). ConclusionOur study confirmed the safety of pTPX in medical inpatients at low risk of bleeding but identified an association between pTPX and HAA. Adherence to guidelines that recommend administering pTPX to medical inpatients at increased venous thromboembolism risk and low bleeding risk is necessary.

How artificial intelligence during the pandemic modified the role of a biomarker as d-dimer

Artificial intelligence (AI) was introduced in medicine to make some difficult decision-making regarding diagnostics and/or treatments easy. Its application derives from the improvement of information obtained with computer sciences and informatics, in particular with information derived by algorithms obtained with special informatics support as machine learning. The scenario of hospital changes induced by the COVID-19 pandemic makes easy the application of AI for some clinical updates. Being lung failure with pulmonary embolism is the most common cause of death for inpatients with COVID-19, some biomarkers such as the d-dimer are constantly used associated with other clinical features in order to improve medical assistance. For this reason, d-dimer during the pandemic changed its traditional use for predictive negative value in patients with suspected pulmonary embolism and took relevance for its values giving the chance to change the intensity of anticoagulation for several inpatients. In most cases, according to data reported from several cohorts, these changes improved the morbidity and mortality of a significant percentage of inpatients with COVID-19. The International medical prevention registry on venous thromboembolism and d-dimer and modified sepsis-induced coagulopathy scores were the most used scores derived from AI and dedicated to these clinical aspects in inpatients with COVID-19. Therefore, this review was dedicated to flexible changes that we can use after d-dimer values in different clinical scenarios that vary from disseminated intravascular coagulation to pulmonary embolism to COVID-19.

Integrating Clinical Decision Support Into Electronic Health Record Systems Using a Novel Platform (EvidencePoint): Developmental Study.

Through our work, we have demonstrated how clinical decision support (CDS) tools integrated into the electronic health record (EHR) assist providers in adopting evidence-based practices. This requires confronting technical challenges that result from relying on the EHR as the foundation for tool development; for example, the individual CDS tools need to be built independently for each different EHR. The objective of our research was to build and implement an EHR-agnostic platform for integrating CDS tools, which would remove the technical constraints inherent in relying on the EHR as the foundation and enable a single set of CDS tools that can work with any EHR. We developed EvidencePoint, a novel, cloud-based, EHR-agnostic CDS platform, and we will describe the development of EvidencePoint and the deployment of its initial CDS tools, which include EHR-integrated applications for clinical use cases such as prediction of hospitalization survival for patients with COVID-19, venous thromboembolism prophylaxis, and pulmonary embolism diagnosis. The results below highlight the adoption of the CDS tools, the International Medical Prevention Registry on Venous Thromboembolism-D-Dimer, the Wells' criteria, and the Northwell COVID-19 Survival (NOCOS), following development, usability testing, and implementation. The International Medical Prevention Registry on Venous Thromboembolism-D-Dimer CDS was used in 5249 patients at the 2 clinical intervention sites. The intervention group tool adoption was 77.8% (4083/5249 possible uses). For the NOCOS tool, which was designed to assist with triaging patients with COVID-19 for hospital admission in the event of constrained hospital resources, the worst-case resourcing scenario never materialized and triaging was never required. As a result, the NOCOS tool was not frequently used, though the EvidencePoint platform's flexibility and customizability enabled the tool to be developed and deployed rapidly under the emergency conditions of the pandemic. Adoption rates for the Wells' criteria tool will be reported in a future publication. The EvidencePoint system successfully demonstrated that a flexible, user-friendly platform for hosting CDS tools outside of a specific EHR is feasible. The forthcoming results of our outcomes analyses will demonstrate the adoption rate of EvidencePoint tools as well as the impact of behavioral economics "nudges" on the adoption rate. Due to the EHR-agnostic nature of EvidencePoint, the development process for additional forms of CDS will be simpler than traditional and cumbersome IT integration approaches and will benefit from the capabilities provided by the core system of EvidencePoint.

Universal EHRs Clinical Decision Support for Thromboprophylaxis in Medical Inpatients: A Cluster Randomized Trial

BackgroundThromboprophylaxis for medically ill patients during hospitalization and postdischarge remains underutilized. Clinical decision support (CDS) may address this need if embedded within workflow, interchangeable among electronic health records (EHRs), and anchored on a validated model. ObjectivesThe purpose of this study was to assess the clinical impact of a universal EHR-integrated CDS tool based on the International Medical Prevention Registry on Venous Thromboembolism plus D-Dimer venous thromboembolism model. MethodsThis was a cluster randomized trial of 4 tertiary academic hospitals from December 21, 2020 to January 21, 2022. Inpatients over age 60 with key medical illnesses were eligible. We embedded CDS at admission and discharge. Hospitals were randomized to intervention (CDS; n = 2) vs usual care (n = 2) groups. The primary outcome was rate of appropriate thromboprophylaxis. Secondary outcomes included venous, arterial, and total thromboembolism, major bleeding, and all-cause mortality through 30 days postdischarge. ResultsAfter exclusions, 10,699 of 19,823 patients were analyzed. Intervention group tool adoption was 77.8%. Appropriate thromboprophylaxis was increased at intervention hospitals, both inpatient (80.1% vs 72.5%, OR: 1.52, 95% CI: 1.39-1.67) and at discharge (13.6% vs 7.5%, OR: 1.93, 95% CI: 1.60-2.33). There were fewer venous (2.7% vs 3.3%, OR: 0.80, 95% CI: 0.64-1.00), arterial (0.25% vs 0.70%, OR: 0.35, 95% CI: 0.19-0.67), and total thromboembolisms (2.9% vs 4.0%, OR: 0.71, 95% CI: 0.58-0.88) at intervention hospitals. Major bleeding was rare and did not differ between groups. Mortality was higher at intervention hospitals (9.1% vs 7.0%, OR: 1.32, 95% CI: 1.15-1.53). ConclusionsEHR-embedded CDS increased appropriate thromboprophylaxis and reduced thromboembolism without increasing major bleeding in medically ill inpatients. Mortality was higher at intervention hospitals.

Overuse and underuse of thromboprophylaxis in medical inpatients

BackgroundThromboprophylaxis (TPX) prescription is recommended in medical inpatients categorized as high risk of venous thromboembolism (VTE) by validated risk assessment models (RAMs), but how various RAMs differ in categorizing patients in risk groups, and whether the choice of RAM influences estimates of appropriate TPX use is unknown. ObjectivesTo determine the proportion of medical inpatients categorized as high or low risk according to validated RAMs, and to investigate the appropriateness of TPX prescription. MethodsThis is a prospective cohort study of acutely ill medical inpatients from 3 Swiss university hospitals. Participants were categorized as high or low risk of VTE by validated RAMs (ie, the Padua, the International Medical Prevention Registry on Venous Thromboembolism, simplified, and original Geneva scores). We assessed prescription of any TPX at baseline. We considered TPX prescription in high-risk and no TPX prescription in low-risk patients as appropriate. ResultsAmong 1352 medical inpatients, the proportion categorized as high risk ranged from 29.8% with the International Medical Prevention Registry on Venous Thromboembolism score to 66.1% with the original Geneva score. Overall, 24.6% were consistently categorized as high risk, and 26.3% as low risk by all 4 RAMs. Depending on the RAM used, TPX prescription was appropriate in 58.7% to 63.3% of high-risk (ie, 36.7%-41.3% underuse) and 52.4% to 62.8% of low-risk patients (ie, 37.2%-47.6% overuse). ConclusionThe proportion of medical inpatients considered as high or low VTE risk varied widely according to different RAMs. Only half of patients were consistently categorized in the same risk group by all RAMs. While TPX remains underused in high-risk patients, overuse in low-risk patients is even more pronounced.

Prediction of bleeding in patients being considered for venous thromboembolism prophylaxis

BackgroundVenous thromboembolism (pulmonary embolism and deep vein thrombosis) is an important preventable cause of in-hospital death. Prophylaxis with low doses of anticoagulants reduces the incidence of venous thromboembolism but can also cause bleeding. It is, therefore, important to stratify the risk of bleeding for hospitalized patients when considering pharmacologic prophylaxis. The IMPROVE (international medical prevention registry on venous thromboembolism) and Consensus risk assessment models (RAMs) are the two tools available for such patients. Few studies have evaluated their ability to predict bleeding in a large, unselected cohort of patients. We assessed the ability of the IMPROVE and Consensus bleeding RAMs to predict bleeding within 90 days of hospitalization in a comprehensive analysis encompassing all hospitalized patients, regardless of surgical vs nonsurgical status. MethodsWe analyzed consecutive first hospital admissions of 1,228,448 unique surgical and nonsurgical patients to 1298 Veterans Affairs facilities nationwide between January 2016 and December 2021. IMPROVE and Consensus scores were generated using data from a repository of their common electronic medical records. We assessed the ability of the two RAMs to predict bleeding within 90 days of admission. We used area under the receiver operating characteristic curves to determine the prediction of bleeding by each RAM. ResultsOf 1,228,448 hospitalized patients, 324,959 (26.5%) were surgical and 903,489 (73.5%) were nonsurgical. Of these patients, 68,372 (5.6%) had a bleeding event within 90 days of admission. The Consensus RAM scores ranged from −5.60 to −1.21 (median, −4.93; interquartile range, −5.60 to −4.93). The IMPROVE RAM scores ranged from 0 to 22 (median, 3.5; interquartile range, 2.5-5). Both showed good calibration, with higher scores associated with higher bleeding rates. The ability of both RAMs to predict 90-day bleeding was low (area under the receiver operating characteristic curve 0.61 for the IMPROVE RAM and 0.59 for the Consensus RAM). The predictive ability was also low at 30 and 60 days for surgical and nonsurgical patients, patients receiving prophylactic, therapeutic, or no anticoagulation, and patients hospitalized for ≥72 hours. Prediction was also low across different bleeding outcomes (ie, any bleeding, gastrointestinal bleeding, nongastrointestinal bleeding, and bleeding or death). ConclusionsIn this large, unselected, nationwide cohort of surgical and nonsurgical hospital admissions, increasing IMPROVE and Consensus bleeding RAM scores were associated with increasing bleeding rates. However, both RAMs had low ability to predict bleeding at 0 to 90 days after admission. Thus, the currently available RAMs require modification and rigorous reevaluation before they can be applied universally.

External Validation of the Padua and IMPROVE-VTE Risk Assessment Models for Predicting Venous Thromboembolism in Hospitalized Adult Medical Patients: A Retrospective Single-Center Study in Japan

Objectives: To assess the external validity of the Padua and International Medical Prevention Registry on Venous Thromboembolism (IMPROVE-VTE) risk assessment models (RAMs) for predicting venous thromboembolism (VTE) within 90 days of admission among hospitalized medical patients in Japan. Materials and Methods: A university hospital cohort comprising 3876 consecutive patients ages ≥15 years admitted to a general internal medicine department between July 2016 and July 2021 was retrospectively analyzed using data extracted from their medical records. Results: A total of 74 VTE events (1.9%), including six cases with pulmonary embolism (0.2%), were observed. Both RAMs had poor discriminative performance (C-index=0.64 for both) and generally underestimated VTE risks. However, recalibrating the IMPROVE-VTE RAM to update the baseline hazard improved the calibration (calibration slope=1.01). Decision curve analysis showed that a management strategy with no prediction model outperformed a clinical management strategy guided by the originally proposed RAMs. Conclusions: Both RAMs require an update to function in this particular setting. Further studies with a larger-sized cohort, including re-estimation of the individual regression coefficients with additional, more context-specific predictors, are needed to create a useful model that would help advance risk-oriented VTE prevention programs.

Twelve-month risk of thromboembolic events in COVID-19 hospital survivors in Scotland.

COVID-19 may predispose patients to arterial and venous thrombotic disorders due to endothelial dysfunction and platelet activation [1]. High rates of in-hospital arterial/venous thromboembolism have been reported [2] and are likely to persist post-discharge. Current UK guidelines suggest prophylactic anticoagulation for a minimum of 7 days, including after hospital discharge [3]. A recent trial found benefit in extending prophylaxis for 35 days after discharge in high-risk patients [4]. We aimed to identify the risk of arterial/venous thromboembolism in a national population in the 12 months after hospital discharge following COVID-19 in order to inform prophylaxis strategies, including anticoagulation decisions and duration. We used routine healthcare data to identify all COVID-19 hospital survivors from the adult Scottish population of 5.5 million and without documented contraindications to anticoagulation (online Supporting Information, Appendix S1), discharged before 23 August 2021. All patients were followed-up until 23 September 2021 or until death. Approval for access to datasets was granted by the Public Benefit and Privacy Panel for Health and Social Care. Our primary outcome was a composite of mortality or hospital readmission for arterial/venous thromboembolism (online Supporting Information, Appendix S1). We used cumulative incidence, accounting for competing risk events, to report mortality and time to first readmission. We stratified our findings by sex and the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) associative score, used to identify high venous thromboembolism risk in acutely ill medical patients for extended thromboprophylaxis (low (0–1), moderate (2–3) and high (4+) risk) [5]. The IMPROVE score comprises seven criteria: previous VTE; known thrombophilia; lower-limb paralysis/paresis; history of cancer; immobilisation ≥ 1 day; critical care stay; and age > 60 y (online Supporting Information, Table S1). The dataset was cleaned and analysed using R v3.6.3 (R Foundation for Statistical Computing, Vienna, Austria). Cell counts < 5 were suppressed. Between 1 February 2020 and 23 August 2021, 22,969 patients were discharged alive from hospital after admission with COVID-19 in Scotland; 22,230 had no contraindications to anticoagulation (Table 1, online Supporting Information, Table S2). The IMPROVE score classified 7494 (37.0%) patients as low risk, 10,844 (53.6%) as moderate risk and 1898 (9.4%) as high risk of VTE. Patients in the high-risk group were older (age 80+ y: high risk 35.1% vs. low risk < 0.1%), and had more comorbidities (2+ Charlson comorbidities: high risk 62.2% vs. low risk 10.0%). Less than 0.1% of the low-risk group were admitted to ICU during their index admission, compared with 19.7% of the moderate-risk group and 10.1% of the high-risk group. 1 n = 7494 2–3 n = 10,844 4+ n = 1898 The overall cumulative incidence for arterial/venous thromboembolism was 1.2% (95%CI 1.1 - 1.4%) at 35 days and 4.1% (95%CI 3.8 - 4.5%) at 12 months (Fig. 1, online Supporting Information, Figs. S1 and S2); however, this rose to 2.3% (95%CI 1.7 - 3.0%) at 35 days and 7.5% (95%CI 6.2 -8.9%) for patients in the high-risk group, and was consistently higher for men than women. Pulmonary embolism was the commonest event resulting in readmission or death across all risk strata (online Supporting Information, Table S3). The arterial/venous thromboembolism events resulting in readmission were significantly higher than those causing death. The rate of events was similar across all strata for the first 30 days (Fig. 1), after which there was a plateau in the low-risk group. However, there was no similar fall in the moderate- or high-risk groups, and the majority of events occurred after 35 days post-discharge. The risk of arterial/venous thromboembolism after discharge from hospitalisation with COVID-19 was high, and considerably greater across all IMPROVE strata compared with the cohort in which the score was derived when restricted to a comparable outcome (VTE 0.4% at 3 months post discharge vs. our cohort VTE incidence of 1.6% (95%CI 1.4 - 1.7%)) [5]. Rates were lower than observed in the enriched control arm of Nishiga et al. [1], where asymptomatic arterial/venous thromboembolism detected by screening accounted for a third of the events. A strength of our study is its population-based approach in a real-world setting, where routine healthcare data can enable identification of clinically significant events. We were unable to account for in-hospital management, such as treatment with steroids or tocilizumab. Even in the low-risk group, the 2.0% risk of arterial/venous thromboembolism at 12 months was high enough to justify offering patients anticoagulation treatment, in line with treatment thresholds for other conditions with thrombotic risk such as atrial fibrillation [6]. Consideration should be given to the role of anticoagulation in all patients with severe COVID-19 when discharged from hospital, with a shared decision-making approach taken when balancing risks of arterial/venous thromboembolism against bleeding. The mechanism of arterial/venous thromboembolism in COVID-19 may include immunothrombosis in addition to the non-immunological venous thromboembolism seen in other conditions, raising the possibility that anticoagulants with anti-inflammatory properties such as heparins may be more effective than direct oral anticoagulants [7]. Although the incidence in the lowest risk group plateaued within the first month, higher risk groups showed no such reduction, and longer-term anticoagulation should be considered for high-risk patients, potentially in line with guidelines suggesting a minimum of 3 months for a provoked pulmonary embolism [8]. The authors acknowledge the support of the eDRIS Team, Public Health Scotland, for its involvement in obtaining approvals, provisioning and linking data and the use of the secure analytical platform within the National Safe Haven. JF and AD are joint first authors; EH and NL are joint last authors. No other competing interests declared. Appendix S1. Methods. Figure S1. Cumulative incidence for arterial/venous thromboembolism (AV-TE) specific readmission and AV-TE specific mortality up to 12 months post hospital discharge. Figure S2. Cumulative incidence for AV-TE specific mortality/readmission stratified by individual strata of IMPROVE score. Table S1. Modified IMPROVE Score, used by MICHELLE trial Investigators. Table S2. Comorbidities and treatment of Scottish hospital COVID-19 survivors without documented contraindications to anticoagulation. Table S3. Cumulative incidence at 12 months for readmission, mortality and composite of readmission and mortality from overall arterial/venous thromboembolism, stroke, acute myocardial infarction, pulmonary embolism, other arterial/venous thromboembolism. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Acute Venous Disease Anomalies in Critically Ill COVID-19 Patients

Introduction: Other entities besides deep vein thrombosis (DVT) affecting the venous system, such as superficial vein phlebitis (SVP) and superficial vein thrombophlebitis (SVT), receive poor attention in the literature. However, both entities may propagate proximally into the deep venous system and progress to a DVT. To our knowledge, the relevance of other venous findings such as SVP or SVT in coronavirus disease 2019 (COVID-19) patients has not been evaluated. This work aimed to assess the clinical, biochemical, and hematological variables associated with the incidence of acute venous diseases, such as DVT, SVP, and SVT, in a cohort of 74 critically ill COVID-19 patients and their association with mortality.Methods: Given the high thrombotic risk, all patients underwent venous imaging with bedside ultrasound. Clinical variables were obtained from medical records. Comparisons were made by the chi-square test or Fisher’s exact test. We constructed Kaplan-Meier curves and used Cox proportional hazard models to calculate hazard ratios for dichotomized risk factors to identify predictors of mortality. SPSS version 21.0 (IBM Corp., Armonk, NY) was used for statistical analysis.Results: SVP occurred in 28 patients (37.8%), DVT in 22 patients (29.7%), and 28 patients died (37.8%). Elevated D-dimer was associated with DVT but not with SVP. Neither SVP nor DVT was associated with mortality. After adjusting for age, elevated troponins (OR: 2.4, 95% CI: 1.1-5.4), platelets < 244 cell/mm3 (2.4, 1.1-5.6), and IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) bleeding score > 7 (2.8, 1.3-6.3) were predictors of mortality.Conclusions: Acute venous findings such as SVP and DVT are highly prevalent and independent of mortality in critically ill COVID-19 patients. These entities are not related, although they may occur synchronically. DVT is frequently presented as an asymptomatic distal bilateral finding associated with elevated D-dimer, decreased ferritin, and higher vasoactive drug use but independent from chronic venous disease. Interestingly, elevated troponins, decreased platelets, and a prognostic value > 7 of the IMPROVE bleeding score were predictors of mortality in this group of critically ill COVID-19 patients.

Bleeding and thrombotic complications in patients with severe COVID-19: A prospective observational study.

The hypercoagulable state plays an important role in the pathophysiology of Coronavirus disease-2019 (COVID-19).1 The clear association between COVID-19 and hypercoagulable state resulted in extensive use of anticoagulant drugs worldwide. However, due to the frequent bleeding events with liberal doses,2 the current recommendations restrict anticoagulant drugs to the prophylactic dose when thrombotic events are not present.3 Yet the benefit of the use of anticoagulant drugs in doses higher than the ordinary prophylactic doses still shows conflicting evidence.4, 5 Hence, reaching the appropriate anticoagulation regimen requires extensive reports for the prevalence of bleeding and thrombosis and identifying possible tools for risk stratification for bleeding. Furthermore, currently, there is no validated score to assess bleeding risk in patients with COVID-19. We aimed in this study to evaluate the prevalence of thrombosis and bleeding in patients with severe COVID-19 and to assess the ability of the International Medical Prevention Registry on Venous Thromboembolism Bleeding risk assessment model (IMPROVE bleed RAM) to predict major bleeding in this population. This prospective observational study was conducted in a university hospital after the institutional Ethics Committee approval (N-124-2021). Written informed consent was obtained from the patient's next-in-kin before the enrollment. We included adult patients (>18 years) with severe COVID-196 within 12 h of admission. Exclusion criteria were age <18 years, patient on anticoagulant therapy before hospital admission, pregnancy, and/or expected death or discharge within 48 h from admission. Demographic (age, sex, body mass index, and Charlson Comorbidity Index), clinical (heart rate, mean arterial pressure, respiratory rate, temperature, peripheral oxygen saturation, Acute Physiology and Chronic Health Evaluation II [APACHE II] score) and laboratory data (Platelet count, international normalizing ratio, C-reactive protein, d-dimer) were collected on admission. Data for the IMPROVE bleed RAM were collected and the score was calculated.7 Anticoagulation therapy was prescribed as follows; Patients with no documented venous thromboembolism were given prophylactic dose of anticoagulation (subcutaneous enoxaparin 40 mg once daily if body mass index < 40 kg/m2 and twice daily if the body mass index > 40 kg/m2). Confirmed venous thromboembolism, arterial thrombotic events, patients who developed atrial fibrillation, and patients on extra-corporeal membrane oxygenation (ECMO), therapeutic anticoagulation was implemented (subcutaneous enoxaparin 0.8 mg/kg twice daily if the body mass index > 40 kg/m2, enoxaparin 1 mg/kg twice daily if creatinine clearance > 30 ml/min, and enoxaparin 1 mg/kg once daily if creatinine clearance < 30 ml/min).3 The primary outcome was the incidence of thrombotic events. Secondary outcomes included the incidence of major bleeding events8 during hospital stay, risk factors for bleeding, and ability of IMPROVE bleed RAM to predict bleeding events. The sample size was planned to detect an incidence of thrombotic disorders of 15% with null hypothesis of 5%. A minimum number of 103 patients would achieve a study power of 95% and an alpha error of 0.05. The number of patients was increased by 110 to compensate for possible dropouts. Categorical data we presented as frequency (percentages) and continuous data are presented as means (standard deviations) or medians (quartiles) as appropriate. Adjusted odds ratio (OR) and their 95% confidence intervals (CIs) for risk factors for bleeding events were identified using the logistic regression analysis. Multivariate analysis included variables with p-value < 0.2 in the univariate analysis. The area under the receiver operating characteristics curve (AUC) was calculated to evaluate the ability of IMPROVE bleed RAM to predict bleeding event. A p-value < 0.05 was significant. Statistical packages for social science software version 21 and MedCalc version 14 were used for data analysis. One-hundred twenty-four patients were screened for eligibility and 10 patients were excluded (5 patients for failure to obtain consent, 4 patients for being already on anticoagulation and 1 patient was pregnant), and 114 patients were included in the final analysis. Baseline characteristics are summarized in Table 1. Deep venous thrombosis (%) Pulmonary embolism (%) STEMI (%) Ischemic stroke (%) MVO (%) All patients were initially provided with oxygen via nonrebreathing mask, and the flow was adjusted to maintain SpO2 > 94%, 58% required high flow nasal oxygen and/or noninvasive mechanical ventilation, 55.3% of patients required mechanical ventilation, and three patients were placed on a veno-venous ECMO. Venous thromboembolic and arterial thrombotic events were observed in 10 (8.8%) and 5 (4.4%), respectively; while, bleeding occurred in 18 (15.8%) patients, 10 (8.8%) patients were classified as major (Table 1). The risk factors for bleeding events were IMPROVE bleed RAM and d-dimer through the univariate analysis (Table 2). However, the multivariate analysis showed that IMPROVE bleed RAM was the only risk factor for major bleeding (Table 2). The AUC (95% CI) of IMPROVE bleed RAM score for predicting bleeding: 0.76 (0.67–0.84), sensitivity: 78 (52–94)%, specificity: 69 (59–78)%, positive predictive value: 32 (24–41)%, negative predictive value: 94 (87–98)%, and a cutoff value > 6.5. In patients with severe COVID-19, we found a considerable prevalence of bleeding events (15.5%) with major bleeding in 8.8% of cases while thrombotic arterial and venous, events were observed in 13.2% of patients. This high prevalence of bleeding was reported despite the conservative use of anticoagulation. Current evidence shows that bleeding in patients with severe COVID-19 pneumonia is not only due to anticoagulation treatment, but also due to microvascular damage.9 In line with our findings, some previous reports showed major bleeding events in critically ill patients with COVID-19 which ranged between 4.8% and 18%.10, 11 In comparison to recent reports,12, 13 current study showed a lower prevalence of thrombotic events. The prevalence of serious thrombotic events (pulmonary embolism and ST-elevation myocardial infarction) was lower than major bleeding events. We evaluated the possible risk factors for bleeding in our patients and found that IMPROVE bleed RAM score was the only independent risk factor. Furthermore, the score showed moderate predictive ability and excellent negative predictive value for bleeding. supporting our findings, Wang et al.14 reported higher IMPROVE bleed RAM score in critically ill patients with COVID-19 in comparison to non-critically ill patients. Our study is the first study to prospectively evaluate the predictive ability to IMPROVE bleed RAM score in patients with severe COVID-19 using univariate, multivariate, and AUC analyses. The optimum dose of anticoagulants for patients with severe COVID-19 is not yet settled, and it is essential to report the prevalence and risk factors of both thrombosis and bleeding to reach the appropriate regimen for anticoagulation in these patients. According to our findings, we suggest that the use of anticoagulant drugs should be judicious as the risk of bleeding might be relatively higher than the risk of thrombosis. IMPROVE bleed RAM score might help in deciding whether to use anticoagulants or not. The current study has some limitations, first, it was conducted in one university; however, we collected the data from three separate units that were handled by different teams of intensivists; this provides more generalizability for our findings. Second, we did not follow up with the patients after discharge from hospital. In conclusion, despite the judicious use of anticoagulant drugs, the risk of bleeding in patients with severe COVID 19 is still considerable and should not be ignored. Being the independent risk factor for bleeding, IMPROVE bleed RAM score could help in guiding anticoagulation plan in these patients. IMPROVE bleed RAM score less than 6.5 can rule out the risk of bleeding with a negative predictive value of 94%. Conceptualization: Mina A. Helmy, Ahmed Hasanin, and Maha Mostafa. Data Curation: Mina A. Helmy, Lydia M. Milad, and Maha Mostafa. Formal Analysis: Mina A. Helmy, Ahmed Hasanin, and Maha Mostafa. Investigation: Mina A. Helmy, Lydia M. Milad, Eman A. Elsayed, Omnia Y. Kamel, Shaimaa Fathy, and Mohamed Elsayad. Methodology: Mina A. Helmy, Lydia M. Milad, Ahmed Hasanin, Eman A. Elsayed, Omnia Y. Kamel, Maha Mostafa, Shaimaa Fathy, and Mohamed Elsayad. Project Administration: Ahmed Hasanin. Resources: Mina A. Helmy, Lydia M. Milad, Eman A. Elsayed, Omnia Y. Kamel, Shaimaa Fathy, and Mohamed Elsayad. Supervision: Mina A. Helmy and Maha Mostafa. Visualization: Mina A. Helmy, Ahmed Hasanin, and Maha Mostafa. Writing – original draft preparation: Mina A. Helmy, Lydia M. Milad, and Ahmed Hasanin. Writing – review and editing: Eman A. Elsayed, Omnia Y. Kamel, Maha Mostafa, Shaimaa Fathy, and Mohamed Elsayad. All authors have read and approved the final version of the manuscript. The corresponding author, Ahmed Hasanin, had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. The corresponding author, Ahmed Hasanin, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. The data that support the findings of this study are available from the corresponding author upon reasonable request.

IMPROVE bleeding score predicts major bleeding in advanced gastrointestinal cancer patients with venous thromboembolism.

The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified. We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding. In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n=40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P=0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients. IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism.

Prevalence and Clinical Characteristics of Proximal Deep Venous Thrombosis After a High-Density Coronavirus Disease 2019 Cluster in a Japanese Psychiatric Hospital.

The prevalence of deep venous thrombosis (DVT) among hospitalized psychiatric patients after coronavirus disease 2019 (COVID-19) infection remains unclear.Methods and Results:We retrospectively investigated the prevalence of proximal DVT after COVID-19 infection among 50 hospitalized patients in a Japanese psychiatric hospital that in which a COVID-19 cluster developed between August and September 2020. The prevalence of proximal DVT was 10.0%. Patients with proximal DVT had a lower body weight and higher maximum D-dimer levels and International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE scores. After COVID-19 infection, hospitalized psychiatric patients are at high risk of DVT and should be carefully followed up.

Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial

BackgroundPatients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown.MethodsIn this open-label, multicentre, randomised trial conducted at 14 centres in Brazil, patients hospitalised with COVID-19 at increased risk for venous thromboembolism (International Medical Prevention Registry on Venous Thromboembolism [IMPROVE] venous thromboembolism [VTE] score of ≥4 or 2–3 with a D-dimer >500 ng/mL) were randomly assigned (1:1) to receive, at hospital discharge, rivaroxaban 10 mg/day or no anticoagulation for 35 days. The primary efficacy outcome in an intention-to-treat analysis was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Adjudication was blinded. The primary safety outcome was major bleeding. The primary and safety analyses were carried out in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04662684.FindingsFrom Oct 8, 2020, to June 29, 2021, 997 patients were screened. Of these patients, 677 did not meet eligibility criteria; the remaining 320 patients were enrolled and randomly assigned to receive rivaroxaban (n=160 [50%]) or no anticoagulation (n=160 [50%]). All patients received thromboprophylaxis with standard doses of heparin during hospitalisation. 165 (52%) patients were in the intensive care unit while hospitalised. 197 (62%) patients had an IMPROVE score of 2–3 and elevated D-dimer levels and 121 (38%) had a score of 4 or more. Two patients (one in each group) were lost to follow-up due to withdrawal of consent and not included in the intention-to-treat primary analysis. The primary efficacy outcome occurred in five (3%) of 159 patients assigned to rivaroxaban and 15 (9%) of 159 patients assigned to no anticoagulation (relative risk 0·33, 95% CI 0·12–0·90; p=0·0293). No major bleeding occurred in either study group. Allergic reactions occurred in two (1%) patients in the rivaroxaban group.InterpretationIn patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis.FundingBayer.

Asymptomatic deep vein thromboses in prolonged hospitalized COVID-19patients.

High incidence of venous thromboembolic (VTE) events in coronavirus disease 2019 (COVID-19) patients has been reported despite pharmacologic thromboprophylaxis. We performed prospective bilateral lower extremity ultrasound evaluation of prolonged hospitalized COVID-19 ward patients from our institution without clinical suspicion of deep vein thrombosis (DVT).A total of 102 patient were included in the study. All patients were receiving pharmacologic thromboprophylaxis, the majority in intermediate or therapeutic doses. Asymptomatic DVT was detected in 26/102 (25.5%) patients: 22 had distal and four had proximal DVT, six had bilateral leg involvement. Pulmonary embolism was highly prevalent (17/70, 24.3%) but similarly grouped among patients with and without asymptomatic DVT. In total 37.2% of patients included in the study were recognized as having VTE.Asymptomatic DVT events were more common in intensive care unit (ICU) survivors (60% in postmechanically ventilated ICU survivors, 21.2% in ward patients, 22% in high-flow oxygen treated patients; P = 0.031), in patients with higher modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk-score (median 3 vs. 2 points with and without DVT; P = 0.021) and higher body temperature on admission (median 38.7 °C vs. 37.7 °C with and without DVT; P = 0.001). No clear associations with Padua VTE risk score, demographic and other clinical characteristics, intensity of thromboprophylaxis, severity of other COVID-19 symptoms, degree of systemic inflammation or D‑dimers on admission were found (P > 0.05 for all analyses).Systematic ultrasound assessment in prolonged hospitalized severe COVID-19 patients prior to hospital discharge is needed, especially in ICU survivors, to timely recognize and appropriately treat patients with asymptomatic DVT.Supplementary InformationThe online version of this article (10.1007/s00508-021-01973-1) contains supplementary material, which is available to authorized users.

Inflammatory Markers and Thromboembolic Risk in Patients with Non-Muscle-Invasive Bladder Cancer

Introduction: Patients with bladder cancer have a high risk of venous thrombosis that represents a key challenge for physicians in the decision-making for initiating anticoagulation therapy. Non-muscle-invasive bladder cancer (NMIBC) represents more than 70% of all diagnosed bladder malignancies; therefore, we aimed to evaluate the relationship of the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and risk of thrombosis by using the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score as well as the risk of bleeding by using the IMPROVE Bleeding Risk Assessment Score in a study cohort. Material and Methods: This was a retrospective observational study involving 130 patients who met the inclusion criteria: age > 18 years, stage pTa-pT1 NMIBC. The exclusion criteria were age < 18 years; stage pT2 or higher; or a presentation of metastasis, inflammatory, liver or autoimmune diseases, or other systemic neoplasms. In order to evaluate the risk of thromboembolic events as well as those of bleeding, the IMPROVE scores were calculated for each patient. Subjects were categorized in a Low IMPROVE group (< 4 points) or a High IMPROVE group. By using uni- and multivariate regression models, we analyzed CBC-derived parameters which could be associated with a higher risk of venous thrombosis in subjects with low or high IMPROVE scores. Results: Patients with IMPROVE score greater than 4 were associated with higher NLR, LMR and lymphocyte values (p < 0.05). In a multivariate regression model, the IMPROVE score was significantly influenced by lymphocyte count (p = 0.007) as well as the NLR value (p < 0.0001). Conclusions: In our study population, subjects with NMIBC with low lymphocytes and NLR > 3 were at a higher risk of developing venous thromboembolic events, reflected by an IMPROVE score of greater than 4. The IMPROVE and IMPROVE Bleeding Risk Assessment Scores are easy to use, and, complemented with the CBC-derived lymphocyte to monocyte ratio as a prothrombotic marker, could aid in the decision of prophylactic anticoagulation therapy during admission.

Association between risk of venous thromboembolism and mortality in patients with COVID-19

ObjectivesTo investigate the association of risk of venous thromboembolism with 30-day mortality in COVID-19 patients. MethodsA total of 1030 COVID-19 patients were retrospectively collected, with baseline data on demographics, sequential organ failure assessment (SOFA) score, and VTE risk assessment models (RAMs), including Padua prediction score (PPS), International Medical Prevention Registry (IMPROVE), and Caprini. ResultsThirty-day mortality increased progressively from 2% in patients at low VTE risk to 63% in those at high risk defined by PPS. Similar findings were observed in IMPROVE and Caprini scores. Progressive increases in VTE risk were also associated with higher SOFA score. High risk of VTE was independently associated with mortality regardless of adjusted gender, smoking status and some comorbidities, with hazard ratios of 29.19, 37.37 and 20.60 for PPS, IMPROVE and Caprini RAM, respectively (P < 0.001 for all comparisons). The predictive accuracy of PPS (area under curve (AUC) 0.900), IMPROVE (AUC 0.917), or Caprini (AUC 0.861) RAM for risk of hospitalized mortality was unexpectedly strong. ConclusionsWe established that the presence of a high risk of VTE identifies a group of COVID-19 patients at higher risk for mortality. Furthermore, there is a high accuracy of VTE RAMs to predict mortality in these patients.