Kreuziger, Lisa Baumann

Introduction: Use of validated risk stratification tools for work up of suspected pulmonary embolism (PE) is an endorsed recommendation of the American Society of Hematology and the American College of Emergency Physicians. Due to variations in clinical practice, electronic health record (EHR) systems, and medical provider trainings, the use, documentation, and implementation of these tools vary widely. Current processes do not allow for electronic capture and quality reporting at most institutions. Methods: We sought to design and implement clinical pre-test probability (PTP) tools at three large healthcare institutions for use in emergency departments (ED). At each site, a hematologist partnered with ED physician leadership and local information technology experts to design and implement PTP tools in clinical workflows. Overall, 38 EDs (high volume tertiary EDs and smaller regional EDs) located in the United States along the East Coast and Midwest regions were involved. A major goal of implementation was integration into clinical workflow and automatic documentation. After design and implementation, awareness and education of the new EHR tool was distributed electronically to ED providers. After implementation, use of PTP tools was analyzed between September 12, 2022 and January 11, 2023. PTP use was examined as percent of visits for which patients underwent CT pulmonary angiography (CTPA). Results: Each institution chose the 3 tier Wells' Score for implementation while one site designed an integrated Wells'/PERC or YEARS score calculator. Two sites implemented the tool as an optional flowsheet and one site implemented the tool as mandatory parameters within the orders for PE imaging studies. The mandatory tool could be bypassed with prespecified selections or if a D-dimer existed within 48 hours . Complete details of the site-specific implementation are shown in Table 1. Over the 4-month evaluation timeframe, there was a total of 270,214 ED encounters. Uptake and utilization of the PTP tools are shown in Table 2. Use of PTP was highest at the site with forced PTP documentation which ranged from 49-53% of ordered CTPAs, compared to Site 2 where use was 2-3%, and Site 1 where use ranged from 1-3%. At Site 1, use of PTP increased slightly over the study period with signs that PE yield on imaging was increasing as well (3.4% to 5.9%). At Site 2, PE yield on imaging was overall high (9-10%), and remained similar with similar use of PTP tools over the study period. Use of PTP and PE yield (6-8%) on imaging also remained similar throughout the study at Site 3. Conclusion: Forced use of PTP within the orders for CTPA led to the highest use of PTP (Site 3) but this did not result in meaningfully higher PE yield on CTPA compared to the other sites. PE yield at each site was at or above the 5% yield for PE on CTPA which has been previously reported. Given that PTP uptake was relatively stable over the measurement period at Site 2 and 3, this indicates the process had mostly stabilized and that other strategies are needed to improve uptake of PTP, reduce utilization of CTPA, and further increase yield on CTPA. Increasing PTP use and rising PE yield at Site 1 demonstrated ongoing potential for improvements past this study timeframe.

Introduction: ASH Guidelines for diagnosis of pulmonary embolism (PE) start with risk assessment using a pretest probability tool (PTP) followed by D-dimer testing or CT pulmonary angiography (CTPA) depending on risk. We aimed to develop an electronic clinical quality measure (eCQM) to encourage broader use of a validated PTP scoring tool in emergency departments (EDs). The Centers for Medicare & Medicaid Services require reporting of eCQMs which consist of value sets or lists of standardized codes linked to patient data within the electronic health record. We sought to identify a standardized way to identify CTPA and abnormal D-dimer tests using administrative codes (i.e. CPT, LOINC, SNOMEDCT codes) across three institutions. Methods: Value sets identifying CTPA and D-dimers were reviewed from existing eCQMs. Three institutions representing 38 EDs from across the country submitted data from all ED encounters between September 12, 2022 and January 11, 2023. Imaging types were reviewed from each of the CPT codes and LOINC (Logical Observation Identifiers Names and Codes). We determined the number of ED encounters, pre-test probability tool use, and diagnosis of PE using different codes. We calculated sensitivity, specificity, positive and negative predictive value (PPV and NPV, respectively). Results: Over the 4-month study period, 270,214 encounters were identified across 38 EDs. Each institution identified CTPA with site-specific codes (Table 1). The Full CTPA Value Set identified 55% more encounters than the site-specific codes (Full set 15,054/9679 site-specific codes). LOINC code 88322-3 was only used at one site. CPT code 71275 had the best sensitivity and specificity, but still had false positives (PPV 82%) (Table 2). D-dimer values were identified as LOINC code 48065-7 and 91556-1 at Site 1 and 48067-3 at Site 2. SNOMEDCT codes were not used at any site despite being the way other eCQMs identify elevated D-dimer results. Different D-dimer tests with different normal ranges were used at each site. All sites did not have an electronically extractable positive indicator for D-dimer. Conclusion: Due to persistent false positives using CPT Code 71275 for identification of CTPA, using this code would lead to inclusion of patients for whom PTP was not required or recommended. Additionally, coding for an abnormal D-dimer test result are not standardized across institutions. Therefore, administrative codes cannot be used to develop eCQMs whose aim is to evaluate whether CTPA is ordered appropriately based on the PTP risk level and laboratory testing.

Introduction Pulmonary Embolism (PE) is a major cause of morbidity and mortality worldwide. Diagnosis is essential as untreated PE has a 30% mortality rate. Currently, computer tomography pulmonary angiogram (CTPA) is the standard of care to diagnose PE. However, this modality is expensive, exposes patients to radiation and increases risk of contrast induced nephropathy. Furthermore, only 5% of CTPAs performed are positive for PE signifying that many unnecessary tests are being performed. To address this gap, Pre-Test Probability (PTP) tools have been developed to safely exclude patients with low risk of PE and limit iatrogenic harm from over testing. Despite the tools being developed over 20 years ago, they are not widely available in electronic health record (EHR) systems and even when they are built in, uptake remains low. Methods Three large integrated health systems using Epic EHR systems across five states (MA, WI. MN, AZ, FL) built electronic PTP assessments into their EHR systems to safely exclude patients with low risk of PE and limit over testing. Two sites made the PTP optional, and one site made it a forced function (providers were forced to complete PTP prior to ordering CTPA unless a D-dimer result was present in the prior 48 hours). To assess the usability of these EHR tools, the team conducted a survey with ED clinicians across the three test sites. The survey was created to identify which PE risk stratification methods were employed by ED clinicians (EHR embedded PTP tool, apps on their phone, web applications like MDcalc, calculations from memory, or if they relied on clinical gestalt), and to identify barriers to using the EHR embedded PTP. Results Site 1 had 47 respondents, Site 2 had 94 respondents, and Site 3 had 16 respondents. Two key findings emerged from the survey (Figure 1). First, clinicians used a variety of risk stratification approaches and few of them documented their risk assessments in structured fields in the medical record. Second, clinical gestalt was the most used PE risk stratification approach, and this was true across all three test sites. In addition, the health system with a PTP prompt before clinicians could proceed with CTPA orders (Site 3) did not have a higher percentage of clinicians who reported using the EHR embedded tool than sites that did not prompt clinicians to fill in the PTP. Clinicians cited a variety of different barriers to using the EHR embedded PTP tool (Table 1). Conclusion While many clinicians indicated intermittent use of PTP criteria to aid in the diagnosis of PE, risk factors and scores from phone apps, web tools, and calculations from memory are unlikely to be documented in the patient's medical record, which means that they are not accessible to all members of the ED care team and cannot be used for electronic clinical quality measure. The biggest hurdles to increasing the use of structured PTP assessments in the ED setting to safely exclude PE and limit iatrogenic harm from over testing are (1) obtaining buy-in from ED clinicians that the PTP tools provide value over clinical gestalt, at least for a subset of patients who could most benefit, and (2) identifying best practices for incorporating PTP tools into EHR systems that make the tools easier to access and use 3) developing and implementing effective education and awareness programs around the PTP tools. This survey adds to the body of literature on PTP assessments in the ED setting and can help inform further research that is needed to continue to improve the diagnosis of PE. Funding: This project is funded in part by the Gordon and Betty Moore Foundation through Grant GBMF10778 to the American Society of Hematology.

Abstract Background Published data on the risk of venous thromboembolism (VTE) with coronavirus disease 2019 (COVID-19) vaccines are scarce and inconclusive, leading to an unmet need for further studies. Methods A retrospective, multicentered study of adult patients vaccinated for one of the three approved COVID-19 vaccines in the United States of America and a pre-COVID-19 cohort of patients vaccinated for influenza at two institutions: Mayo Clinic Enterprise sites and the Medical College of Wisconsin, looking at rate of VTE over 90 days. VTE was identified by applying validated natural language processing algorithms to relevant imaging studies. Kaplan–Meier curves were used to evaluate rate of VTE and Cox proportional hazard models for incident VTE after vaccinations. Sensitivity analyses were performed for age, sex, outpatient versus inpatient status, and type of COVID-19 vaccine. Results A total of 911,381 study subjects received COVID-19 vaccine (mean age: 56.8 [standard deviation, SD: 18.3] years, 55.3% females) and 442,612 received influenza vaccine (mean age: 56.5 [SD: 18.3] years, 58.7% females). VTE occurred within 90 days in 1,498 (0.11%) of the total 1,353,993 vaccinations: 882 (0.10%) in the COVID-19 and 616 (0.14%) in the influenza vaccination cohort. After adjusting for confounding variables, there was no difference in VTE event rate after COVID-19 vaccination compared with influenza vaccination (adjusted hazard ratio: 0.95 [95% confidence interval: 0.85–1.05]). No significant difference in VTE rates was observed between the two cohorts on sensitivity analyses. Conclusion In this large cohort of COVID-19-vaccinated patients, risk of VTE at 90 days was low and no different than a pre-COVID-19 cohort of influenza-vaccinated patients.

Background Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. Objective These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about thrombophilia testing. Methods ASH formed a multidisciplinary guideline panel covering clinical and methodological expertise and minimizing bias from conflicts of interest. The McMaster University GRADE Centre provided logistical support, performed systematic reviews, and created evidence profiles and evidence-to-decision tables. The Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE) was used. Recommendations were subject to public comment. Results The panel agreed on 23 recommendations regarding thrombophilia testing and associated management. Nearly all recommendations are based on very low certainty in the evidence due to modeling assumptions. Conclusions The panel issued a strong recommendation against testing the general population before starting combined oral contraceptives (COCs) and conditional recommendations for thrombophilia testing in the following scenarios: (a) patients with VTE associated with nonsurgical major transient or hormonal risk factors; (b) patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued; (c) individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy; (d) pregnant women with a family history of high-risk thrombophilia types; and (e) patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE. For all other questions, the panel provided conditional recommendations against testing for thrombophilia.

Abstract Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Abstract Standard treatment of catheter-associated upper extremity deep vein thrombosis (UE-DVT) is anticoagulation, although catheters are often removed for this indication. The optimal time for catheter removal and whether the act and/or timing of catheter removal is associated with pulmonary embolism (PE) remain unknown. A retrospective cohort study was performed at 8 participating institutions through the Venous thromboEmbolism Network US. Patients with hematologic malignancies and central venous catheter (CVC)–associated UE-DVT were included from 1 January 2010 through 31 December 2016. The primary outcome was objectively confirmed PE within 7 days of UE-DVT diagnosis in anticoagulated patients comparing early (≤48 hours) vs delayed (>48 hours) catheter removal. A total of 626 patients were included, among whom 480 were treated with anticoagulation. Among anticoagulated patients, 255 underwent early CVC removal, while 225 had delayed or no CVC removal; 146 patients received no anticoagulation, among whom 116 underwent CVC removal alone. PE within 7 days occurred in 2 patients (0.78%) with early removal compared with 1 patient (0.44%) with delayed or no CVC removal (P > .9). PE or any cause of death within 7 days occurred in 3 patients in both the early removal (1.18%) and delayed/no removal (1.33%) groups (P > .9). In patients treated with CVC removal only (no anticoagulation), there were no PEs but 3 deaths within 7 days. In patients with hematological malignancy and CVC-associated UE-DVT, early removal of CVCs was not associated with an increased risk of PE compared with delayed or no removal.

Introduction The United States Thrombotic Microangiopathy (USTMA) Consortium consists of high-volume US referral centers that are committed to collaborative research in TMAs. The USTMA Immune Thrombotic Thrombocytopenic Purpura (iTTP) registry has compiled retrospective data on demographics, treatments and outcomes in patients with iTTP to create the world's largest database of patients with this rare disease. While there is consensus on the use of therapeutic plasma exchange (TPE) for treatment of iTTP, there are no large randomized trials on which to base use of rituximab. The drug is frequently used for refractory or relapsed iTTP, but is currently being used more frequently for de novo (first episode) iTTP. We queried the USTMA iTTP registry to determine whether relapse free survival (RFS) is superior when rituximab is added to TPE and corticosteroids for treatment of iTTP. We hypothesized that the addition of rituximab would improve RFS at 5 years in both de novo and relapsing iTTP. Methods Following IRB approval at each institution, investigators independently reviewed individual patient records to confirm diagnostic criteria and entered demographic, treatment and outcomes data into the REDCap database housed at the University of North Carolina. The diagnosis of iTTP was defined as ADAMTS13 < 10% or ADAMTS13 < 20% with an inhibitor or antibody detected at any point or a clinical diagnosis of iTTP based on presenting characteristics, response to treatment and/or relapsing phenotype before ADAMTS13 testing became available (N=173). Relapse was defined as a recurrence of iTTP after at least 30 days of remission (recurrence within 30 days was considered an exacerbation, or continuation of the prior episode). To explore the effect of rituximab added to TPE and corticosteroids, we first assessed the treatment effect in de novo iTTP patients and then separately in relapse. We constructed Kaplan-Meier curves to compare RFS for patients treated with rituximab plus corticosteroids versus corticosteroids alone in both groups, and compared RFS at specific time points using the Klein method. To better understand whether other patient variables had an effect on RFS in both de novo episodes and relapses, ordinary (time-to-event) and mixed-effects (recurrent time-to-event) Cox proportional hazards models were used to examine the relationships of treatment, race/ethnicity, sex, age, treatment year, and presenting signs/symptoms with the outcome. Analyses were conducted using R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Results As of July, 2019, the USTMA database contains 775 unique study patients with a confirmed diagnosis of iTTP with 1397 unique iTTP episodes. The treatment of patients' de novo iTTP episode was available for analysis in 375 patients, 188 of whom were treated with corticosteroids alone, 131 with corticosteroids plus rituximab, and 56 with other therapies. RFS was significantly higher in patients treated with corticosteroids and rituximab compared to those treated with corticosteroids alone at 1 year (0.93 vs. 0.78, p=0.0002) and 3 years (0.82 vs. 0.66, p=0.004) but not 5 years (0.60 vs. 0.56, p=0.39). In addition, the risk of relapse decreased with later treatment year for de novo iTTP (hazard ratio (HR) 0.95, 95% CI 0.92-0.99, p=0.03), consistent with rituximab use increasing over time, and was increased in African Americans compared with Caucasians (HR 1.83, 1.10-3.06, p=0.02). We then explored the treatment effect in all iTTP relapses (743 relapses in 426 patients). Here, a significant (p=0.0007) interaction between treatment and race was found. Among African Americans, we found no difference in RFS when rituximab was added (HR 1.15, 0.81-1.62, p=0.43). However, among Caucasians, RFS was significantly improved when rituximab was added (HR 0.15, 0.06-0.35, p<0.0001). Conclusions For de novo iTTP, adding rituximab to corticosteroids for immunosuppression likely delays but does not prevent relapse. Unlike in de novo disease, in patients with relapsed iTTP, we found a novel and significant interaction between race and treatment: while Caucasians had significantly improved RFS with the addition of rituximab, there was no effect on RFS in African Americans. Further investigation is warranted to determine the mechanisms of this difference in the response to rituximab in relapsed iTTP to improve outcomes in African Americans. Figure Disclosures Marshall: Sanofi: Membership on an entity's Board of Directors or advisory committees. Farland:Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Imara: Other: PI on Clinical trial- Sickle cell ; Shire: Other: PI on clinical trial Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Zheng:Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding; Ablynx/Sanofi: Consultancy, Speakers Bureau; Alexion: Speakers Bureau. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Off Label Disclosure: rituximab for immunosuppression in TTP.