Multi-ancestry polygenic risk scores for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE.

Genome-wide investigation of exogenous female hormones, genetic variation, and venous thromboembolism risk.

BACKGROUND: Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT). OBJECTIVES: To investigate the potential for genetic predisposition to VTE in OC or HT users, we conducted a gene-by-environment case-only meta-analysis of genome-wide association studies (GWAS). METHODS: Use or nonuse of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and submultiplicative/supramultiplicative gene-by-environment interactions were estimated. The SI parameters were first meta-analyzed across OC and HT studies and subsequently meta-analyzed to obtain an overall estimate. The primary analysis was agnostic GWAS and interrogated all imputed genotypes using a P value threshold of <5.0 × 10-8; secondary analyses were candidate-based. RESULTS: The VTE case-only OC meta-analysis included 2895 OC users and 6607 nonusers; the case-only HT meta-analysis included 2434 HT users and 12 793 nonusers. In primary GWAS meta-analyses, no variant reached genome-wide significance, but the smallest P value approached statistical significance: rs9386463 (P = 5.03 × 10-8). We tested associations for 138 candidate variants and identified 2 that exceeded statistical significance (0.05/138 = 3.62 × 10-4): F5 rs6025 (P = 1.87 × 10-5; SI, 1.29; previously observed) and F11 rs2036914 (P = 2.0 × 10-4; SI, 0.91; new observation). CONCLUSION: The candidate variant approach to identify submultiplictive/supramultiplicative associations between genetic variation and OC and HT use identified a new association with common genetic variation in F11, while the agnostic interrogations did not yield new discoveries.

Intermediate-Risk and High-Risk Pulmonary Embolism: Recognition and Management: Cardiology Clinics: Cardiac Emergencies.

Pulmonary embolism (PE) is the third most common cause of cardiovascular death. Every specialty of medical practitioner will encounter PE in their patients, and should be prepared to employ contemporary strategies for diagnosis and initial risk-stratification. Treatment of PE is based on risk-stratification, with anticoagulation for all patients, and advanced modalities including systemic thrombolysis, catheter-directed therapies, and mechanical circulatory supports utilized in a manner paralleling PE severity and clinical context.

Management of high-risk pulmonary embolism in the emergency department: A narrative review.

BACKGROUND: High-risk pulmonary embolism (PE) is a complex, life-threatening condition, and emergency clinicians must be ready to resuscitate and rapidly pursue primary reperfusion therapy. The first-line reperfusion therapy for patients with high-risk PE is systemic thrombolytics (ST). Despite consensus guidelines, only a fraction of eligible patients receive ST for high-risk PE. OBJECTIVE: This review provides emergency clinicians with a comprehensive overview of the current evidence regarding the management of high-risk PE with an emphasis on ST and other reperfusion therapies to address the gap between practice and guideline recommendations. DISCUSSION: High-risk PE is defined as PE that causes hemodynamic instability. The high mortality rate and dynamic pathophysiology of high-risk PE make it challenging to manage. Initial stabilization of the decompensating patient includes vasopressor administration and supplemental oxygen or high-flow nasal cannula. Primary reperfusion therapy should be pursued for those with high-risk PE, and consensus guidelines recommend the use of ST for high-risk PE based on studies demonstrating benefit. Other options for reperfusion include surgical embolectomy and catheter directed interventions. CONCLUSIONS: Emergency clinicians must possess an understanding of high-risk PE including the clinical assessment, pathophysiology, management of hemodynamic instability and respiratory failure, and primary reperfusion therapies.

A Novel Tool for Predicting an Abnormal Echocardiogram in Patients with Pulmonary Embolism: The PEACE Score.

BACKGROUND: Transthoracic echocardiography (TTE) is an essential tool for risk-stratifying patients with pulmonary embolism (PE), but its availability is limited, often requiring hospitalization. Minimal research exists evaluating clinical and laboratory criteria to predict lack of abnormal TTE findings. OBJECTIVE: We aimed to identify predictors associated with abnormal TTE results in patients with PE to potentially identify those safe for early discharge. METHODS: In this retrospective study, we analyzed an existing database of patients with venous thromboembolism (VTE) at two academic emergency departments, including adult patients with confirmed PE who underwent TTE. The primary goal was to develop and validate a score predicting abnormal TTE, defined as presence of one of the following: right ventricle (RV) dilatation or hypokinesis, septal flattening, right heart thrombus in transit, or ejection fraction < 50%. Variables were demographic characteristics, symptoms, computed tomography (CT) RV strain, troponin T, and N-terminal prohormone of brain natriuretic peptide (NTproBNP). Stepwise logistic regression was used to identify variables independently associated with abnormal TTE. Model discrimination was evaluated using area under the curve (AUC) of the receiver operating characteristic curve. A clinical prediction rule was developed. RESULTS: 530 of 2235 patients were included; 56% (297 of 530) had an abnormal TTE. The following six variables were independently associated with abnormal TTE: dyspnea, dizziness, troponin T ≥ 0.1 ng/mL, NTproBNP > 900 pg/mL, CT RV strain, and nonsubsegmental PE. A clinical prediction rule using these six criteria yielded scores between 0 and 7, performing well with AUC of 0.80 (95% CI 0.79-0.80). A score of 1 was 99.7% sensitive in identifying no abnormality. A score ≥ 5 was 98% specific for an abnormality. CONCLUSIONS: The PEACE (Pulmonary Embolism and Abnormal Cardiac Echocardiogram) criteria, composed of six variables, is highly effective in predicting abnormal TTE in patients with PE, potentially identifying who is safe for early discharge from the hospital.

Multi-ancestry polygenic risk scores for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium GWAS meta-analyses of European- (71,771 cases and 1,059,740 controls) and African-ancestry samples (7,482 cases and 129,975 controls). We used LDpred2 and PRSCSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6,261 cases and 88,238 controls) and African-ancestry sample (1,385 cases and 12,569 controls). Multi-ancestry PRSs with weights tuned in European- and African-ancestry samples, respectively, outperformed ancestry-specific PRSs in European- (PRSCSXEUR: AUC=0.61 (0.60, 0.61), PRSCSX_combinedEUR: AUC=0.61 (0.60, 0.62)) and African-ancestry test samples (PRSCSXAFR: AUC=0.58 (0.57, 0.6), PRSCSX_combined AFR: AUC=0.59 (0.57, 0.60)). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS may be used to identify individuals at highest risk for VTE and provide guidance for the most effective treatment strategy across diverse populations.

Validation of Echocardiographic Measurements in Patients with Pulmonary Embolism in the RIETE Registry.

Background In acute pulmonary embolism (PE), echocardiographic identification of right ventricular (RV) dysfunction will inform prognostication and clinical decision-making. Registro Informatizado Enfermedad TromboEmbolica (RIETE) is the world's largest registry of patients with objectively confirmed PE. The reliability of site-reported RV echocardiographic measurements is unknown. We aimed to validate site-reported key RV echocardiographic measurements in the RIETE registry. Methods Fifty-one randomly chosen patients in RIETE who had transthoracic echocardiogram (TTE) performed for acute PE were included. TTEs were de-identified and analyzed by a core laboratory of two independent observers blinded to site-reported data. To investigate reliability, intraclass correlation coefficients (ICCs) and Bland-Altman plots between the two observers, and between an average of the two observers and the RIETE site-reported data were obtained. Results Core laboratory interobserver variations were very limited with correlation coefficients >0.8 for all TTE parameters. Agreement was substantial between core laboratory observers and site-reported data for key parameters including tricuspid annular plane systolic excursion (ICC 0.728; 95% confidence interval [CI], 0.594-0.862) and pulmonary arterial systolic pressure (ICC 0.726; 95% CI, 0.601-0.852). Agreement on right-to-left ventricular diameter ratio (ICC 0.739; 95% CI, 0.443-1.000) was validated, although missing data limited the precision of the estimates. Bland-Altman plots showed differences close to zero. Conclusion We showed substantial reliability of key RV site-reported measurements in the RIETE registry. Ascertaining the validity of such data adds confidence and reliability for subsequent investigations.

Addressing the rising trend of high-risk pulmonary embolism mortality: Clinical and research priorities.

BACKGROUND: Deaths from high-risk pulmonary embolism (PE) appear to have increased in the US over the last decade. Modifiable risks contributing to this worrisome trend present opportunities for physicians, researchers, and healthcare policymakers to improve care. METHODS: We sought to contextualize contemporary, high-risk PE epidemiology and examine clinical trials, quality improvement opportunities, and healthcare policy initiatives directed at reducing mortality. RESULTS: We observed significant and modifiable excess mortality due to high-risk PE. We identified several opportunities to improve care including: (1) rapid translation of forthcoming data on reperfusion strategies into clinical practice; (2) improved risk stratification tools; (3) quality improvement initiatives to address presumptive anticoagulation practice gaps; and (3) adoption of health policy initiatives to establish pulmonary embolism response teams and address the social determinants of health. CONCLUSION: Addressing knowledge and practice gaps in intermediate and high-risk PE management must be prioritized and informed by forthcoming high-quality data. Implementation efforts are needed to improve acute PE management and resolve treatment disparities.

Right-to-left ventricular ratio is higher in systole than diastole in patients with acute pulmonary embolism.

OBJECTIVES: In acute pulmonary embolism (PE), the right ventricle (RV) may dilate compromising left ventricular (LV) size, thereby increasing RV/LV ratio. End-diastolic RV/LV ratio is often used in PE risk stratification, though the cause of death is RV systolic failure. We aimed to confirm our pre-clinical observations of higher RV/LV ratio in systole compared to diastole in human patients with PE. METHODS: We blinded and independently analyzed echocardiograms from 606 patients with PE, evaluated by a Pulmonary Embolism Response Team. We measured RV/LV ratios in end-systole and end-diastole and fractional area change (FAC). Our primary outcome was a composite of 7-day clinical deterioration, treatment escalation or death. Secondary outcomes were 7-day and 30-day all-cause mortality. RESULTS: RV/LV ratio was higher in systole compared to diastole (median 1.010 [.812-1.256] vs. .975 [.843-1.149], p < .0001). RV/LV in systole and diastole were correlated (slope = 1.30 [95% CI 1.25-1.35], p < .0001 vs. slope = 1). RV/LV ratios in both systole and diastole were associated with the primary composite outcome but not with all-cause mortality. CONCLUSION: The RV/LV ratio is higher when measured in systole versus in diastole in patients with acute PE. The two approaches had similar associations with clinical outcomes, that is, it appears reasonable to measure RV/LV ratio in diastole.

Low concordance between CTPA and echocardiography in identification of right ventricular strain in PERT patients with acute pulmonary embolism.

PURPOSE: Right ventricular strain (RVS) is used to risk stratify patients with acute pulmonary embolism (PE) and influence treatment decisions. Guidelines suggest that either computed tomography pulmonary angiography (CTPA) or transthoracic echocardiography (TTE) can be used to assess RVS. We sought to determine how often CTPA and TTE yield discordant results and to assess the test characteristics of CTPA compared to TTE. METHODS: We analyzed data from a single-center registry of PE cases severe enough to warrant activation of the hospital's Pulmonary Embolism Response Team (PERT). We defined RVS as a right ventricular to left ventricular ratio (RV/LV) ≥ 1 or radiologist's interpretation of RVS on CTPA or as the presence of either RV dilation, hypokinesis, or septal bowing on TTE. RESULTS: We included 554 patients in our analysis, of whom 333 (60%) had concordant RVS findings on CTPA and TTE. Using TTE as the reference standard, CTPA had a sensitivity of 95% (95% CI 92-97%) and a specificity of 4% (95% CI 2-8%) for identifying RVS. CONCLUSIONS: In a selected population of patients with acute PE for which PERT was activated, CTPA is highly sensitive but not specific for the detection of RVS when compared to TTE.

Barriers and facilitators to interhospital transfer of acute pulmonary embolism: An inductive qualitative analysis.

Background: Interhospital transfer (IHT) of patients with acute life-threatening pulmonary embolism (PE) is necessary to facilitate specialized care and access to advanced therapies. Our goal was to understand what barriers and facilitators may exist during this transfer process from the perspective of both receiving and referring physicians. Methods: This qualitative descriptive study explored physician experience taking care of patients with life threatening PE. Subject matter expert physicians across several different specialties from academic and community United States hospitals participated in qualitative semi-structured interviews. Interview transcripts were subsequently analyzed using inductive qualitative description approach. Results: Four major themes were identified as barriers that impede IHT among patients with life threatening PE. Inefficient communication which mainly pertained to difficulty when multiple points of contact were required to complete a transfer. Subjectivity in the indication for transfer which highlighted the importance of physicians understanding how to use standardized risk stratification tools and to properly triage these patients. Delays in data acquisition were identified in regards to both obtaining clinical information and imaging in a timely fashion. Operation barriers which included difficulty finding available beds for transfer and poor weather conditions inhibiting transportation. In contrast, two main facilitators to transfer were identified: good communication and reliance on colleagues and dedicated team for transferring and treating PE patients. Conclusion: The most prominent themes identified as barriers to IHT for patients with acute life-threatening PE were: (1) inefficient communication, (2) subjectivity in the indication for transfer, (3) delays in data acquisition (imaging or clinical), and (4) operational barriers. Themes identified as facilitators that enable the transfer of patients were: (1) good communication and (2) a dedicated transfer team. The themes presented in our study are useful in identifying opportunities to optimize the IHT of patients with acute PE and improve patient care. These opportunities include instituting educational programs, streamlining the transfer process, and formulating a consensus statement to serve as a guideline regarding IHT of patients with acute PE.

Calendar month variation in the diagnosis and severity of pulmonary embolism.

BACKGROUND: Pulmonary embolism (PE) is the third-leading cause of cardiovascular death in the United States, and several studies suggest PE shows seasonal variation. Variation in monthly PE diagnosis may be due to pathophysiologic factors or confounding/bias. However, severe PE may be less prone to diagnostic bias. To address this gap, we analyzed two registries from 1/2013-12/2018 with the aim of describing temporal trends in PE diagnosis and severity. METHODS: We performed a retrospective analysis of two existing databases containing: (1) consecutive patients diagnosed with PE in the emergency departments (EDs) of two large, urban teaching hospitals, and (2) severe PEs requiring PE Response Team (PERT) activation at one of the above hospitals. The primary outcome was to assess variation in PE diagnosis and severity by calendar month. Separate analysis of these two databases sought to control for workup bias by trainee experience across the academic year. One-way ANOVA and Poisson regression were performed to assess for cyclical variation across calendar months, using Stata v16.1. RESULTS: The PE diagnosis database contained 1324 patients over 36 months. One-way ANOVA did not reveal a statistically significant (p = 0.713) association between calendar month and PE number. The PERT activation database contained 1082 patients over 72 months. One-way ANOVA revealed a statistically significant (p = 0.024) association between calendar month and activations, repeated year-on-year. CONCLUSION: Our results indicate correlation between calendar month and PERT activation; however, this pattern was not observed for PE diagnoses. This finding warrants further investigation into the causes of calendar month variation of PERT activations.

SARS-CoV-2 Positivity in Ambulatory Symptomatic Patients Is Not Associated With Increased Venous or Arterial Thrombotic Events in the Subsequent 30 Days.

BACKGROUND: COVID-19 has been associated with increased risk of thromboembolism in critically ill patients. OBJECTIVE: We sought to examine the association of SARS-CoV-2 test positivity and subsequent acute vascular thrombosis, including venous thromboembolism (VTE) or arterial thrombosis (AT), in a large nationwide registry of emergency department (ED) patients tested with a nucleic acid test for suspected SARS-CoV-2. METHODS: The RECOVER (Registry of Potential COVID-19 in Emergency Care) registry includes 155 EDs across the United States. We performed a retrospective cohort study to produce odds ratios (ORs) for COVID-19-positive vs. COVID-19-negative status as a predictor of 30-day VTE or AT, adjusting for age, sex, active cancer, intubation, hospital length of stay, and intensive care unit (ICU) care. RESULTS: Comparing 14,056 COVID-19-positive patients with 12,995 COVID-19-negative patients, the overall 30-day prevalence of VTE events was 1.4% vs. 1.3%, respectively (p = 0.44, χ2). Multivariable analysis identified that testing positive for SARS-CoV-2 status was negatively associated with both VTE (OR 0.76; 95% confidence interval [CI] 0.61-0.94) and AT (OR 0.51; 95% CI 0.32-0.80), whereas intubation, ICU care, and age 50 years or older were positively associated with both VTE and AT. CONCLUSIONS: In contrast to other reports, results from this large, hetereogenous national sample of ED patients tested for SARS-CoV-2, showed no association between vascular thrombosis and COVID-19 test positivity.

Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation.

Background: Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which the adverse metabolic component of obesity contributes to disease compared to the non-metabolic components is often uncertain. We aimed to use Mendelian randomisation (MR) and specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects on diseases. Methods: We selected 37 chronic diseases associated with obesity and genetic variants associated with different aspects of excess weight. These genetic variants included those associated with metabolically 'favourable adiposity' (FA) and 'unfavourable adiposity' (UFA) that are both associated with higher adiposity but with opposite effects on metabolic risk. We used these variants and two sample MR to test the effects on the chronic diseases. Results: MR identified two sets of diseases. First, 11 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here, MR with the FA and UFA genetics showed opposing effects on risk of disease: coronary artery disease, peripheral artery disease, hypertension, stroke, type 2 diabetes, polycystic ovary syndrome, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout. Second, 9 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) are likely a cause. Here, MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, both indicated higher disease risk: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-oesophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism. Conclusions: Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects, including the risks to individuals with high body mass index who may be relatively metabolically healthy. Funding: Diabetes UK, UK Medical Research Council, World Cancer Research Fund, National Cancer Institute.

Oral postmenopausal hormone therapy and genetic risk on venous thromboembolism: gene-hormone interaction results from a large prospective cohort study.

OBJECTIVE: Oral postmenopausal hormone therapy (HT) has been shown to be associated with venous thromboembolism (VTE), but whether this association is modified by VTE-associated genetic susceptibility is unknown. We examined interactions between oral HT use and a genetic risk score (GRS) of VTE. METHOD: Eligible women were postmenopausal women who had data on oral HT use, VTE incidence between 1990 and 2012, and genetic data in the Nurses' Health Study. We built a GRS aggregating 16 VTE-related genetic variants. We used Cox regression to estimate associations of HT use with incident VTE and assessed interactions between HT use and VTE GRS. We also estimated incidence of VTE between age 50 and 79 years for groups of women defined by HT use and VTE GRS. RESULTS: We identified 432 incident VTE cases. Current HT users were at higher risk of VTE than never users (HR: 1.9, 95% CI: 1.5-2.6), with slightly higher risk for estrogen plus progestin HT than estrogen only (HR: 2.4 vs 1.9). The GRS was associated with VTE risk (HR comparing 4th quartile to 1st: 2.0, 95% CI: 1.2-3.4). We did not observe significant multiplicative interactions between HT use and GRS. The estimated VTE risk difference (per 10,000 person-years) comparing 50-year-old current HT users to never users was 22.5 for women in the highest GRS quartile and 9.8 for women in the lowest GRS quartile. CONCLUSION: The VTE GRS might inform clinical guidance regarding the balance of risks and benefits of HT use, especially among younger women.

Predicting factors for pulmonary embolism response team activation in a general pulmonary embolism population.

Pulmonary embolism response teams (PERT) aim to improve treatment of acute pulmonary embolism (PE). PERT focus on intermediate- and high-risk PE patients, but recent multicenter studies show that low-risk PE patients compose one in five of all PERT cases. Conversely, not all intermediate- and high-risk PE patients elicit a PERT activation. The factors leading to PERT activations remain unknown. This study aims to describe the patient characteristics associated with PERT activation for low-risk PE patients and characteristics precluding PERT activation for intermediate/high-risk PE patients. We analysed data from all patients with confirmed PE diagnosed in the Massachusetts General Hospital Emergency Department from August 2013 to February 2017 and cross-referred these data with patients who received a PERT activation and patients who did not. Patients were stratified into low-risk or intermediate/high-risk PE. Univariate analyses were performed within each risk group comparing patients with a PERT activation and patients without. Fifteen percent (56/374) of low-risk PE patients triggered a PERT activation. Patient characteristics associated with PERT activation were: (1) vascular disease, (2) pulmonary diseases, (3) thrombophilia, (4) current use of anticoagulants, (5) central PE and (6) concurrent DVT. Thirty-five percent (110/283) of intermediate/high-risk PE patients did not elicit a PERT activation. Patient characteristics precluding a PERT activation were: (1) vascular disease, (2) malignancies and (3) asymptomatic presentation. Low-risk PE patients with PERT activations had more extensive clot burden, complex comorbidities, or had failed anticoagulation treatment. Intermediate/high-risk PE patients without PERT activations tended to have malignancies or vascular disease.