NEWS & EVENTS

State of the Science in Acute and Chronic Manifestations of Pulmonary Embolism Virtual Workshop

November 5 - 6, 2020
Virtual Zoom Event

Description

Background

Pulmonary embolism (PE) and the related condition of venous thromboembolism (VTE) carry a substantial public health burden due to the current necessity for life-long clinical management. There are clear clinical risk factors for acute PE, but the risk factors and pathogenic events leading to the subsequent development of chronic thromboembolic disease (CTED), chronic thromboembolic pulmonary hypertension (CTEPH), and post-PE syndrome are much less clear. Addressing PE’s underlying disease process requires a multidisciplinary approach and many specialties and subspecialties. Additionally, there is a need to forge stronger connections and interaction among basic, translational, and clinical scientists studying PE and related conditions while considering the patient perspective and the role of implementation science. 

On November 5–6, 2020, the National Heart, Lung, and Blood Institute (NHLBI) virtually convened a multidisciplinary group of scientists to discuss the state of the science of the acute and chronic manifestations of PE. The scientists were experts in hematology, coagulation, pulmonology, cardiac surgery, general and interventional radiology, general and interventional cardiology, critical care, and emergency medicine. Their research interests covered the spectrum from basic to translational to clinical and implementation science. Prior to the meeting, these experts formed five working groups (WGs) and discussed the state of the science and research opportunities in the areas of hematology, interventional radiology, cardiology/cardiac surgery, pulmonology, and emergency medicine/critical care medicine. On Day 1, WGs presented their findings, an expert shared her personal experience as a patient, and participants discussed a range of topics related to PE. On Day 2, participants formed concurrent breakout groups to discuss the most significant knowledge gaps in five types of research—basic, translational, clinical (diagnostic), clinical (therapeutic), and implementation science—and how work in those areas might address the crucial problems in the field.

The goals of the meeting were (1) to critically evaluate the state of knowledge regarding cutting-edge approaches to the diagnosis and management of acute PE; (2) to identify gaps in knowledge regarding prevention and resolution of PE versus transition to CTED and further evolution to CTEPH and right ventricular (RV) failure; (3) to help define  opportunities for future research directions; and (4) to communicate workshop findings – knowledge gaps, research opportunities, and perceived needs – to the community of heart, lung, and blood investigators.

The findings, knowledge gaps, and opportunities described below represent a summary of individual opinions and ideas expressed during the workshop.  The summary does not represent any sort of consensus or directive, nor does it represent an expression of research priorities or intended research directions for NHLBI or NIH.

Reports From the Working Groups (Day 1) 

Hematology

Evidence on the natural history of PE (mostly from the peri-operative setting) suggests that it falls within a continuous spectrum of clotting conditions  now known as venous thromboembolism (VTE), which also includes deep vein thrombosis (DVT). Specific risk factors for VTE differ across clinical phenotypes and scenarios. This introduces the possibility that clot structures may differ as well, and that clots in the pulmonary circulation that look the same radiographically may be very different etiologically. For example, pulmonary artery thrombosis (PAT) in situ may be a manifestation of local inflammation-driven coagulation. Therefore, alternative therapy may be beneficial. 

The WG presented characteristics of an ideal animal model of PE (e.g., large animal that allows measurement of pulmonary artery pressure, lung function, and hemodynamic and biochemical responses). Current mouse models of PE are used mostly to study DVT formation, stability, and embolization rather than PE and its effects on lung function. Current non-mouse models of PE have many shortcomings. Although there is an urgent need to develop a large-animal model of PE, the suitability of a model depends on the aspect of PE studied.

With an estimated 8 million acutely ill medical patients at risk of VTE hospitalized annually in the United States (https://pubmed.ncbi.nlm.nih.gov/17626254/), there is a significant unmet medical need for VTE prevention in this population, especially post-hospital discharge. Antithrombotic guidelines recommend individualized VTE and bleed risk assessment (https://pubmed.ncbi.nlm.nih.gov/30482763/). Electronic alerts and risk assessment at patient discharge can increase prophylaxis and decrease VTE (https://pubmed.ncbi.nlm.nih.gov/15758007/), and the expanding use of tools such as SMART (Substitutable Medical Applications, Reusable Technologies) could further enhance the prevention of VTE.

Research Opportunity: VTE Risk Assessment Model validation and implementation in different systems is an important area for future research.

In severe PE, there is a vicious cycle—inflammation activates platelets and coagulation, causing thrombosis, which furthers inflammation. Heparin may improve results, but research is needed on whether dual pathway inhibition would offer additional benefits. There is general agreement that patients with PE who have ongoing, significant risk factors should remain on indefinite anticoagulation. Patients with PE who have transient, resolved risk factors can be treated with a short course. Many clinicians extend therapy in patients with PE in comparison with identical patients without identified PE. Many patients with PE undergo serial imaging to look for “clot resolution.” There are a number of long-term complications of PE (e.g., symptoms of reduced functional status). A crucial question is: What is the post-PE syndrome? It includes persistent clinical symptoms, with impaired functional status and quality of life and affects half of patients. But there is a lack of consistent correlation with measurable abnormalities in venous anatomy or function. Post-PE syndrome is not well-studied, inconsistently diagnosed, and lacks available evidence-based therapies.

Research Gaps:

  • Research is needed to define PE versus PAT in situ.
  • Studies should follow PE patients for chronic long-term complications. 
  • Regarding post-PE syndrome, determine the relative contributions of deconditioning versus persistent anatomic/physiologic abnormalities of the lungs and RV. 
  • Research should determine whether systemic thrombolysis or local interventional approaches to acute PE decrease the incidence of the post-PE syndrome. High-quality, large multicenter randomized controlled trials (RCTs) with patient-relevant clinical endpoints are needed to address this important issue in patients with intermediate-risk PE.

Interventional Radiology

The current PE stratification model from the European Society of Cardiology (ESC) (2019) has many shortcomings (e.g., it does not identify which patients are at high risk for deterioration from submassive to massive PE, nor does it identify patients who would benefit from advanced therapies). Importantly, this model does not incorporate long-term disability, and long-term outcomes are particularly crucial in PE. PE patients have reduced peak oxygen consumption 6 months to 1 year after PE, with 30–50 percent exhibiting reduced functional capacity. 

Risk stratification has not become more precise because basic and translational PE research are underdeveloped. Because animal models of acute and chronic PE are inadequate, the pathophysiology of PE is incompletely understood. Beyond standard imaging (e.g., echocardiography and computed tomography [CT] scan), biomarker research is lacking—with no dynamic or continuous biomarker available. Additionally, there are insufficient correlations between biomarkers, presentation characteristics, and short- and long-term outcomes. There is a lack of data on how advanced therapies affect long-term outcomes. Additionally, there is no consensus on the most important outcomes in PE. 

The future PE risk stratification model needs to identify (1) submassive PE patients who are at high risk for short-term deterioration and death based on new biomarkers and scores, (2) patients who are at highest risk for long-term disability, and (3) patients who will benefit from advanced therapies beyond anticoagulation.

Regarding the current state of catheter therapy for severe PE, systemic thrombolysis has promise, but causes too much bleeding, as shown by the Pulmonary Embolism International Thrombolysis (PEITHO) Study. Catheter-directed thrombolysis (CDT) is also used to treat severe PE. The Ultrasound Accelerated Thrombolysis of Pulmonary Embolism (ULTIMA) study, the only randomized trial vs. anticoagulation alone, found that CDT reduced RV/left ventricle (LV) ratio to a greater extent than heparin at 24 hours. The SEATTLE II study found that CDT was associated with RV/LV ratio reduction and a 10 percent major bleeding rate. Clot extraction minus fibrinolytic is another option. After ULTIMA, interventional trials have not included a control group, thus, it is unknown how new devices compare to the best medical therapy. There are many data gaps—clinical, technical, and basic and translational science—surrounding catheter therapies. It is not clear whether inferior vena cava (IVC) filters prevent PE or reduce mortality. Better animal models would allow researchers to determine how filters interface with the IVC wall as well as their thrombogenicity. 

Catheter devices for PE represent a tremendous innovation but lack fundamental data. With about 20,000 procedures performed annually and a market cap of 200,000, industry-sponsored trials will not answer the most fundamental PE questions. Many of these trials lack randomization and clinical outcomes data.

Research Opportunities: 

  • A rigorous, feasible randomized trial of CDT for PE with short and long-term clinical outcomes would generate useful knowledge. Using the ATTRACT trial for DVT as a model, a similar PE trial would:
    • Clarify the natural history of PE, especially in the long-term;
    • Identify novel risk factors (e.g., blood biomarkers, baseline characteristics, hemodynamic parameters) for the development of long-term disability and short-term deterioration; and
    • Offer biological insights that would drive research toward new pharmaceuticals and medical devices.
  • Pilot RCTs could answer fundamental, granular questions (e.g., enhanced vs. non-enhanced CDT, non-lytic vs. lytic, short- vs. long-term outcomes).
  •  Consensus is needed on the design, methodology, and endpoints for interventional PE trials.
  • There is a need to capture any and all adverse events for new devices entering the market.
  • There are scientific opportunities for translational biology work, focusing on acute vs. chronic thrombus, through better animal models.

Cardiology/Cardiac Surgery

There are a number of pressing unmet needs regarding diagnosis of acute PE. These include a lack of public awareness of PE symptoms and risk factors. Although diagnostic tests are good, they involve only imaging CT and ventilation–perfusion (VQ) scans, with an index of suspicion. However, the age of thrombus is difficult to determine, and CT scans with contrast are not ideal in young women and individuals with renal failure. 

The age of a thrombus can be difficult to determine even on direct visual inspection, and it is hard to distinguish between acute PE versus acute-on-chronic PE. Clots organize in different ways from point to point in the body. Some patients on anticoagulants show incomplete reabsorption of clots. The assessment of patients as candidates for surgery and the operation to remove clots was briefly described. This patient population has a high risk for stroke because of circulatory arrest (bloodless field is needed). Reduction of pulmonary vascular resistance and complete extraction (must remove the distal tails of clots) are key to good long-term outcomes in these patients. The post-operative complications of PE can be tricky. Therefore, medical teams need protocols in place to prevent pulmonary reperfusion injury. High cardiac output is undesirable in these patients, which runs counter to teaching. 

Diagnosis of the chronic manifestations of PE, such as CTED/CTEPH, presents unique problems. VQ scans are considered the gold standard, but positive VQ scans can occur with subsegmental/non-surgical disease. CT scanning is insufficient to diagnose PE in smaller vessels. In this case, pulmonary angiogram is required. Additionally, only 1–2 percent of patients develop CTEPH after acute PE. For half of patients, there is no clear index of PE. The low incidence is likely confounded by the relative lack of diagnostic tests performed. A challenge is that the best approach to treatment is unclear for patients with CTED who do not have pulmonary hypertension. Additionally, other conditions (e.g., fibrosing mediastinitis, sarcoma/tumor, and vasculitis) have clinical and radiological features similar to CTEPH. Finally, insurance coverage for PE imaging is not consistent across payors.

Patient subgroups with greatest management challenges include individuals with massive PE, severe respiratory failure, and cardiogenic shock. The condition of patients with intermediate risk is also challenging to manage, as well as those with contraindications to lytic therapy and anticoagulation. Additionally, PE is difficult to manage in patients with multiple comorbidities (e.g., high body mass index, hostile chest, and renal failure). 

The field faces many knowledge gaps for CTED/CTEPH. An overarching issue is that there is very limited basic science in CTEPH, and animal models are challenging. It is not clear whether pulmonary thromboendarterectomy is better than balloon pulmonary angioplasty plus medication and whether a hybrid procedure could play a role. More data are needed on the optimal use of pulmonary vasodilators and the best choice of anticoagulant (warfarin or direct oral anticoagulants [DOACs]). The optimal long-term treatment for CTED is not yet known.

Researchers need to address many questions about PE response teams (PERTs)—such as the best structure and scalability, as the expertise may not be available in all but the largest programs. PERTs also raise the issue of de-skilling of the primary team. Additionally, outcome and process measures are needed for PERTs. 

Clinicians have observed varying phenotypes of acute PE (macrovascular vs. microvascular thrombosis) in patients with COVID-19. Many COVID-19 patients show evidence of RV dysfunction. Performing diagnostic tests in COVID-19 patients, as they are often too sick to be moved and contamination must be limited, can be challenging and lead to delays. COVID-19 patients are more prothrombotic, yet optimal anticoagulation regimens are unknown. These patients also can be reluctant to go to the hospital for acute PE treatment, and follow-up tends to be limited. 

Pulmonary

Current risk classifications for PE are: (1) low, (2) intermediate, and (3) high, but there is ambiguity about how to manage intermediate- and high-risk patients, given their significant heterogeneity despite increasing recognition of the risk conferred with RV strain. There is an opportunity for better phenotyping subgroups of intermediate- and high-risk PE on the basis of systolic blood pressure below 90; syncope; chronic RV dysfunction and low RV reserve; comorbidities; and severity of respiratory failure on presentation. Current risk stratification is based on risk scores (e.g., PESI) and imaging (CT and echocardiogram), and is heavily reliant on assessing 30-day mortality risk. There are opportunities to refine and standardize risk stratification algorithms by considering additional biomarkers or imaging parameters (not only RV); “post-therapeutics” or “pre-discharge” risk stratification; and the use of long-term functional outcomes, post-PE syndrome, and CTED/CTEPH in addition to mortality. 

While there are animal models of acute PE that involve graded microsphere injection, large animal models of intermediate- and high-risk PE are needed. Currently, multiple chronic PE models are available. Genetic mouse models of impaired clot resolution and angiogenesis all require a second hit and have variable disease development timeline. Other models involve the injection of ceramic, polystyrene, and glass beads, but these do not duplicate impaired thrombus resolution seen in human CTEPH. Current models of autologous clot injection typically resolve due to rapid lysis. The limitations of current models include that they do not duplicate impaired thrombosis resolution, development of thrombi and emboli, and partial resolution. Models exist for clot formation and resolution, but they are missing assessment of RV function. Animal models of PE must address sex differences and investigate whether they are hormonally regulated, and the age of the animal model must be analogous to that of the patient population.

COVID-19 VTE is an area that needs intensive research in multiple areas. The mechanism of hypercoagulability remains poorly understood. Studies should examine whether this hypercoagulability is driven by platelets, the coagulation cascade, inflammation, or fibrinolysis. Research should determine the particular anticoagulant agents that are best for prophylaxis (unfractionated heparin versus low molecular weight heparin versus DOAC versus acetylsalicylic acid). Studies are also needed to examine the optimal anticoagulants for treatment and whether the choice of agent depends on the severity of respiratory failure. The duration of prophylaxis post-hospital discharge must also be identified. Work is needed to understand post-COVID-19 syndrome (i.e., Long COVID), such as the long-term sequelae of COVID-19 VTE and microthrombosis and whether addressing VTE/microthrombosis affects outcomes. Another important research area is whether the increased incidence of CTED/CTEPH in this patient population partially explains exercise intolerance.

To address the challenge of recognizing CTED/CTEPH, there should be a nationwide focus on developing education initiatives, leveraging technologic advancements (e.g., artificial intelligence, machine learning) to assist in diagnostic capabilities, and targeting appropriate medical organizations to deliver findings. Research should focus on elucidating the post-PE disease spectrum and the transition from acute to chronic thromboembolic disease and patients who are at risk. 

Clinical Guidance Gap: The field needs a summary of best practices in critical care management (e.g., vasopressors, volume resuscitation, and intubation).

Research Opportunities:

  • A great deal of knowledge would be generated from a large-scale RCT among intermediate-high risk PE patients to examine anticoagulants versus catheter-directed lysis versus mechanical thrombectomy and determine which patients will benefit from CDT.
  • A patient registry and associated studies would help to better understand right-heart thrombi (RHT) disease and treatment. This research could determine the incidence of RHT in the intermediate-high and high-risk groups and the best therapies (surgery versus systemic lytics versus half-dose lytics versus aspiration thrombectomy).
  • A national data and biorepository, along with specific criteria for Centers of Excellence, would facilitate the evaluation and management of patients with CTED and CTEPH and help determine the appropriate treatment options and long-term outcomes associated with current therapies.
  • A COVID-19 registry would help scientists examine the impact of the disease on the incidence and expression of CTED states.
  • Research on PERTs should not be limited to academic centers, as they are not representative. Rather, studies should span multiple contexts (i.e., community, rural hospitals). Centers of Excellence for PE care (serving as the hub of a hub-and-spoke model) offer an opportunity to study PERTs, improve health care disparities, and disseminate knowledge. Education/knowledge dissemination on PERTs is needed.

Emergency/Critical Care Medicine 

There are more than 10 million emergency department encounters for dyspnea or chest pain annually. Missed/delayed diagnosis of PE is a major cause of death and disability. Clinicians weigh the risks of missed diagnosis and over testing. Despite improvements during the past two decades, there have been many recent challenges—such as an aging population, obesity, increase in complex care for some conditions, and COVID-19. 

Outstanding Research Questions about Diagnosis:

  • What are the difficulties in diagnosis in particular settings (children, racial disparities, and pregnancy)?
  • Do we have a good understanding of missed diagnosis rate and the resulting harms and economic effects? 
  • Do we have a way to define overdiagnosis? What is the significance of isolated subsegmental PE? Is there a type of “diagnosed” PE for which anticoagulation has more harm than benefit?

COVID-19 confounds PE diagnosis and may warrant empiric anticoagulation. COVID-19 complicates the standard approach to the clinical consideration of PE, as these patients have a great deal of dyspnea, chest discomfort, and anxiety. Researchers need to determine the additive thrombotic effect of moderate-severe COVID-19 and the driving factors. Studies should determine whether ambulatory patients benefit from prophylactic anticoagulants, which patients are good candidates, and the duration of treatment. Studies of COVID-19 survivors are needed to identify the impact of clots on patients with lasting cardiopulmonary impairments. 

Pediatric PE presents a particular challenge, in part due to a lack of research activity compared to adult PE. Indeed, EINSTEIN Junior is one of the only published large, prospective studies that examined the epidemiology, diagnosis, or treatment of children with PE. Pediatric PE diagnosis requires a “high index of suspicion.” PE in children is a rare event, but the incidence of this condition is increasing. Pediatric PE is under-diagnosed (4.2 percent on autopsy), with a bimodal presentation (neonates and adolescents). Major knowledge gaps include that testing and treatment algorithms have been extrapolated from adults, a lack of clinical trials in childhood PE, and a need for prospective studies with sufficient sample sizes. 

Patients yearn for control over recurrence, answers, options, and reassurance during the transition of care. There is a lack of evidence to create “right size” treatment. People expect that outpatient treatment of PE has a lower cost and results in enhanced patient perception of wellness, yet high-quality evidence is lacking. There are many challenges for transitions in VTE across care settings. Multiple anticoagulant agents for VTE—DOACs, warfarin, low molecular weight heparin—are available and effective. But questions remain about considerations between classes and medications within a class, as well as addressing the needs of unique subpopulations. There are also financial concerns about anticoagulants. Over diagnosis is an issue for isolated subsegmental PE, and there is a lack of evidence on this particular condition. 

When and how to perform reperfusion for submassive (or intermediate risk) PE remains a subject of intense debate, with little direct research. Clinicians face quandaries regarding reperfusion therapy, as there has not been a dose-finding trial for systemic lysis. Treatment options are expanding, and no clear mortality benefit has been demonstrated for lysis. Clinical practice guidelines from ESC and the American College of Clinical Pharmacy recommend against lysis without hypotension, but both include latitude for clinician discretion. In submassive PE, patients die from either progressive RV failure from the first PE or a second insult from DVT that embolizes to an already strained RV. The Prevention of Recurrent Pulmonary Embolism by Vena Cava Interruption (PREPIC-2) study examined IVC filters in PE and concomitant DVT. Simplified PESI (Pulmonary Embolism Severity Index) scores were fairly low. In this study, RV strain was only one of many factors that made patients eligible for inclusion, and most enrolled due to age or other comorbidities. A PREPIC-3 study that includes patients with PE and concomitant DVT who have positive biomarkers and evidence of RV strain may be warranted.

In theory, PERTs may reduce practice variability and increase transparency of decision-making. However, the evidence of such effects is lacking. Key research questions about PERTs include the following: (1) Do PERTs improve patient-centered outcomes, and what are the costs versus benefits? (2) Which patients benefit from PERTs? (3) Do PERTs improve transitions of care from inpatient to outpatient settings? Implementing PERTs presents challenges, as there is a lack of consensus as to what defines one of these teams and their key aspects. PERTs are multidisciplinary, rapid-response teams for PE, but they vary greatly across programs. It is difficult to separate the effects of PERTs from the interventions they implement, and the appropriate outcomes for studying them have not been established. The expansion of the PERT model may make comparison to “standard care” difficult. 

The cause of persistent perfusion defects, and when, why, and how they transition to produce CTEPH remains poorly understood. It may be possible to better predict who is most likely to develop CTEPH or CTED after acute PE. Imaging, biomarkers, and patient history may help clinicians better recognize and differentiate acute PE from acute-on-chronic PE and the acute presentation of CTEPH. Current data do not support thrombolysis to prevent CTEPH. 

Little work has been done to determine the role of race, socioeconomic class, and geographic location on missed or delayed diagnosis and nonstandard treatment. However, black adults have a higher incidence of PE compared with whites. Among pediatric PE patients, the mortality for black children is more than double that of whites. More data are needed on the presence of testing inequities for race, ethnicity or gender as there is with other acute disease, as well as the role of social determinants of health on PE incidence, mortality, morbidity, and recurrence. Other research gaps include a lack of data on the link between clinician demographics and testing, diagnosis, and outcomes of PE, as well as racial/ethnic differences in use of reperfusion therapy. Rates of CTEPH by gender and race/ethnicity in the United States should be determined, as much of the existing data on this condition are from Europe.

The Patient Perspective

Moderator: Rana Awdish, M.D., Henry Ford Health System/Wayne State
Speaker: Laura Spece, M.D., M.S., University of Washington

Dr. Laura Spece shared her experience as a person who survived a submassive PE and large DVT in her leg. Dr. Rana Awdish offered her perspective as a person who survived critical illness with multiple complications. Their experiences speak to the importance of patient-centered outcomes in general and in the specific case of PE. Clinicians should recognize that patients—even ones with medical training and knowledge of PE—are busy with their lives, jobs, and families and may deny, misattribute, or expect PE symptoms to resolve. Making things even more challenging for patients, symptoms can be very non-specific, so it can be really difficult to know when or even if treatment should be sought. The experience of PE can be traumatic and filled with anxiety for patients and their families. 

A stressful aspect of the patient experience is that the U.S. health system is fragmented and difficult to navigate. Patients experience long waits for scans and delays in diagnosis and anticoagulant treatment. Even those with good health plans have prescriptions rejected by insurance companies. After hospital discharge, people must deal with a complicated outpatient system with multiple tests and specialist follow-up appointments. For those with access to care—which many people do not have—it is difficult to navigate the system. The financial impacts are significant, even for those with insurance.

Patients can experience difficulty psychologically adjusting to PE, particularly a loss of identity and constant worry about their health, functioning, and family members. They may ask the existential question: Why did this happen to me? Patients may experience the five stages of grief post-PE and need to talk with peers, as they may find it difficult to speak about their feelings with clinicians. Clinicians can help patients have a better experience by “holding the patient in personhood” and reflecting who they are back to them during acute hospitalization. It is also crucial for clinicians to be empathetic, validate patients’ experiences, spend time with them, and make space for their struggles. Clearly communicating a plan to manage care and keep patients as safe as possible can help reassure them. Clinicians should also pay attention to family members and their experiences, and recognize the mental health/support needs of patients. Post-PE syndrome and post-traumatic stress disorder are significant experiences that should be considered and addressed. Post-PE or clot clinics may be helpful, and peer support groups (including virtual meetings) may also be beneficial.

Breakout Session Reports (Day 2) 

Basic Science

Major basic science initiatives are needed to advance our understanding of thromboembolic disease. Animal models for PE, CTEPH, and device/endothelium interactions are greatly needed. Small animal models will advance the study of the vein wall-thrombus interface. Large animal models are required to assess hemodynamic changes in PE. Current models of bleeding and thrombosis lack standardization and do not allow the assessment of microcirculation, which limits our understanding. Special populations that should be accurately represented in preclinical models include transgenic models, males and females, aged and non-aged, individuals with comorbidities (e.g., atherosclerotic, diabetic mice), and pregnancy and other special conditions.

The breakout group noted that many research opportunities would stem from a multicenter biorepository for acute PE/CTEPH that broadly shares specimens (e.g., tissues, peripheral blood samples, time-course sampling after the PE event, circulating biomarkers, samples for thrombin assay, phenotype, and additional clinical information) collected in a standardized manner. The organization of such a repository should emphasize collaboration between basic scientists and clinicians. 

Researchers should test novel potential therapeutic targets and strategies, particularly dual pathway inhibition (anti-platelets and anticoagulants). Inhibition of the inflammatory response seems particularly important for addressing PE in COVID-19 patients. Addressing endothelial cell damage and neutrophil extracellular traps are therapeutic approaches worth pursuing. The area of in situ PAT presents valuable research questions that could be addressed in models of infection, such as influenza and COVID-19.

Translational Science

The creation of a biorepository (i.e., a biologically enhanced registry of VTE cases) would have the greatest impact on the field. The repository should include clinical data from electronic medical records, multiple biological samples from acute and chronic PE patients (particularly related to the transition from acute to chronic PE), blood clots, endothelium, urine (useful for metabolomics), echocardiograms (longitudinal throughout care), and short- and long-term outcomes. Such a biorepository would facilitate the development of a better-defined phenotype for high-risk acute PE, the understanding of the transition from acute to chronic PE (particularly CTEPH), and indications of which patients should or should not receive an intervention. Another benefit of a biorepository is that it would advance -omics approaches for the development of biomarkers for prediction and cut-offs, novel treatments, and the understanding of heterogeneity among PE patients. Finally, a biorepository would improve knowledge about the physiology of clots that do not resolve over time. 

Following the example of the pulmonary hypertension repository (which has harmonized data), big data and machine learning approaches will help address problems presented by PE. Specifically, these approaches would help improve assessment of bleeding risk in general and as it relates to the use of DOACs. However, there are barriers to the establishment of a biorepository of VTE cases. Researchers need to define appropriate outcomes—that is, develop a standard definition of bad outcomes and move toward patient-centered outcomes. A biorepository would be costly, but has enormous potential to improve the understanding and treatment of PE.

Clinical (Diagnostic) 

Research is needed to distinguish between diagnostically acute PE, recurrent PE, acute-on-chronic disease, and chronic disease. Information is also needed to characterize better the natural history of PE. Diagnosis affects enrollment in trials and the deployment of therapies. A focus of research should be identifying biomarkers that can diagnose chronic disease. The chronicity of symptoms and clinical history are also important, but it can be challenging to capture this information with sufficient accuracy and time resolution.

The entire spectrum of PE in children is poorly understood and in need of further study in virtually all aspects. In part because of its relative rarity, pediatric PE is particularly challenging to study or consider clinically. PE in very young children is not necessarily the same as the condition in adolescents. Idiopathic clots are rare in young children.

A key research question is: What diagnostic tests in intermediate/high-risk patients predict short-term outcomes? Biomarker-based diagnostics need to be specific, dynamic, predictive, and quantitative. The limitations of B-type natriuretic peptide and troponin are known. Hemodynamic versus respiratory decompensation may offer diagnostic information. Other major research gaps include the deconvolution of comorbidities and their contributions to diagnostic challenges and outcomes in the acute and chronic settings. Research is needed on ways to reduce diagnostic delays, which is a major issue and affects decisions about how testing is conducted and which patients receive tests. It is important to understand the reasons underlying the known disparities (e.g., sex, gender, race, and ethnicity) in diagnostic delays.

Using “passive” large-scale data (e.g., electronic health record data) can improve short-term risk prediction for acute and chronic PE. But opportunities for use of artificial intelligence/machine learning approaches will require large datasets and a reference standard. Taking a multicenter approach with combined multiple types of data may offer a major opportunity to advance the field. Coordinated efforts are needed and will have all of the challenges associated with “big data” unification and analysis.

Education may be a major underutilized tool in the diagnosis of PE. Community clinicians should be educated on the optimal immediate use of anticoagulation, risk counseling, broadening differential diagnoses, and narrowing differential diagnoses. A public health campaign to educate people on VTE and its symptoms and consequences may be useful. Human factors research has great potential for improving diagnosis of this condition. 

Currently, standard imaging approaches for acute thromboembolic disease are often less robust for distinguishing chronic disease. Diagnostic confusion may be more common than the field currently appreciates, with some particularly challenging clinical situations, such as tumor thrombus versus bland clot. Advanced perfusion imaging may be of limited utility, although it could potentially benefit non-radiologists. Innovative radiopharmaceuticals and combined diagnostic approaches may improve PE diagnosis. Imaging is one part of the diagnostic puzzle. End organ dysfunction and injury is a key consideration that could be addressed by real-time, longitudinal status monitoring of patients, perhaps using mobile health technologies. Information from such monitoring could be used to improve clinical decision-making and risk stratification.

Clinical (Therapeutic) 

Because the safety of CDT and catheter devices is unclear, a definitive clinical trial would go a long way to anchor future treatment, with the additional benefit of elucidating the biology, natural history, and prognosis of PE. Strict exclusion criteria will negatively affect generalizability and enrollment. The current landscape of single-arm trials is limiting innovations in clinical care and evidence-based guidelines.

Currently, trials enroll lower-risk patients, who are unlikely to need advanced intervention, and future trials should focus on populations with a high event-rate likelihood. The ideal study population would have a high enough risk, but would meet inclusion criteria for enrollment and fit within the time constraints of a clinical trial. Regarding clinical trial design, a cluster randomized trial design would offer some advantages given the different expertise at the various centers. Additionally, a more advanced adaptive design (e.g., a 2x2 factorial design) is needed to (1) test an interventional approach versus anticoagulation and (2) randomly assign treatment versus placebo. A current limitation is the expectation for clinical trial outcomes—i.e., reduction in mortality is hard to prove and is not the only thing that matters to patients. The field needs to embrace endpoints that are patient-centered and clinically relevant. A consensus working group is needed to validate and decide on the endpoints and the standards and definitions used. Rigorous endpoints are crucial for a trial that can be defended, endorsed, and helpful with the development of guidelines. Comprehensive endpoints will allow a design without a sham arm.

Clinicians could improve their use of imaging information from emergency department patients to recommend treatment. Improvements in nomenclature would facilitate risk stratification. Although high risk is defined by clinical guidelines, biomarkers would advance the field. One option is to use mHealth to examine recovery from PE continuously throughout a trial, rather than taking measurements at finite timepoints.

Implementation Science

Promising areas for implementation science include information technology support and informatics. Clinical decision support tools that incorporate validated risk assessments and standardized platforms that are agnostic to electronic health records will be helpful. Development and implementation of care bundles and system processes will also improve care. Attention is needed to the organization and structure of care. Centers of Excellence for PE care and team science could provide implementation science frameworks to help tailor care delivery to particular patients and contexts. PERTs have great promise and could be implemented more widely through a hub-and-spoke model as part of knowledge dissemination. Research is needed on shared decision-making (e.g., anticoagulation choice and duration) and communication with PE patients.

Implementation has multiple research gaps that must be addressed. Patient-centered needs assessments are necessary across contexts and stakeholders. Future work should identify the determinants of high-quality PE care, specifically how to avoid alarm fatigue and address skepticism. Determining clinical workflows and reducing disparities are focal areas for studies of PE care quality. Research should determine how clinicians can tailor care for subgroups of PE patients. It will be essential to understand how providers work in their local contexts to identify the necessary supports and best ways to promote culture change. This work should consider care for PE in under-resourced and rural areas. Finally, post-PE care has significant knowledge gaps. 

Following the maxim, “What gets measured gets managed,” the field needs to develop outcome measures. These measures should be patient-centered and include ones related to process. To identify missed opportunities, outcomes should capture the potential value gained and harm reduced from under- or over-diagnosis and under- or over-treatment. Outcome measures need to reinforce delivery of high-quality, evidence-based care. They can also help ensure equitable delivery of care and shape policy.

Implementation scientists should consider the design of validation studies for risk assessment tools and PERTs and the best way to determine effectiveness. Pragmatic, hybrid, cluster-randomized, and stepped-wedge designs seem most appropriate for this area. For efficiency, researchers should collect implementation outcomes within ongoing trials. Partnerships between implementation scientists, multidisciplinary teams, and government agencies will facilitate these studies. 

Workshop Co-Chairs
Kim Kerr, M.D., University of California, San Diego, Pulmonary/Critical Care Co-Chair
Sam Goldhaber, M.D., Brigham and Women’s Hospital and Harvard Medical School, Hematology Co-Chair 
Michael Zhen-Yu Tong, M.D., Cleveland Clinic, Cardiology/Cardiac Surgery Co-Chair

Working Group (WG) Members
Hematology WG
Sam Schulman, M.D., Ph.D., FRCPC (WG Lead), McMaster University 
Mark Crowther, M.D., M.Sc., McMaster University
Nigel Key, M.D., University of North Carolina
Nigel Mackman, Ph.D., University of North Carolina
Alex Spyropoulos, M.D., Northwell Health

Interventional Radiology WG
Akhilesh Sista, M.D. (WG Lead), New York University Grossman School of Medicine 
Jeremy C. Durack, M.D., M.S., Memorial Sloan Kettering Cancer Center
Sanjay Misra, M.D., Mayo Clinic
Matthew S. Johnson, M.D., Indiana University 
John A. Kaufman, M.D., M.S., Oregon Health & Science University
Suresh Vedantham, M.D., Washington University in St. Louis 
Fedor Lurie, M.D., Ph.D., Jobst Vascular Institute

Cardiology/Cardiac Surgery WG
Michael Zhen-Yu Tong, M.D. (WG Lead), Cleveland Clinic, Cardiology/Cardiac Surgery Co-Chair
Ray Benza, M.D., The Ohio State University
Jack Haney, M.D., Duke Health
Gregory Piazza, M.D., M.S., Brigham and Women’s Hospital
Sudarshan Rajagopal, M.D., Ph.D., Duke University
Ashwin Ravichandran, M.D., St. Vincent Hospital Indianapolis
Christopher Solerno, M.D., St. Vincent Hospital Indianapolis
Laura Spece, M.D., M.S., University of Washington
Yoshida Toyoda, M.D., Ph.D., Temple University

Pulmonary WG
Rich Channick, M.D. (WG Lead), University of California, Los Angeles
William Auger, M.D., Temple University
Naomi Chesler, Ph.D., University of California, Irvine
Sara Hegab, M.D., Henry Ford Health System
Laura Spece, M.D., M.S., University of Washington
Belinda Rivera-Lebron, M.D., M.S.C.E., University of Pittsburgh

Emergency/Critical Care Medicine WG 
Jeff Kline, M.D. (WG Lead), Indiana University School of Medicine
Daniel Mark Courtney, M.D., M.S., UT Southwestern Medical Center
Angela Ellison, M.D., M.Sc., Children’s Hospital of Philadelphia
Timothy Fernandes, M.D., M.P.H., University of California, San Diego
Chris Kabrhel, M.D., M.P.H., Massachusetts General Hospital
Kim Kerr, M.D., University of California, San Diego
Kelly Sawyer, M.D., M.S., University of Pittsburgh School of Medicine
Laura Spece, M.D., M.S., University of Washington

NHLBI Staff Workshop Organizers
Josh Fessel, M.D., Ph.D., Division of Lung Diseases (co-lead)
Andrei L. Kindzelski, M.D., Ph.D., Division of Blood Diseases and Resources (co-lead)
Marissa Miller, D.V.M., M.P.H., Division of Cardiovascular Sciences
Kathleen Fenton, M.D., M.S., Division of Cardiovascular Sciences
Susan Shero, RN, M.S., Center for Translation Research and Implementation