International Clinical Practice Guideline Recommendations for Acute Pulmonary Embolism: Harmony, Dissonance, and Silence.

Despite abundant clinical innovation and burgeoning scientific investigation, pulmonary embolism (PE) has continued to pose a diagnostic and management challenge worldwide. Aging populations, patients living with a mounting number of chronic medical conditions, particularly cancer, and increasingly prevalent health care disparities herald a growing burden of PE. In the meantime, navigating expanding strategies for immediate and long-term anticoagulation, as well as advanced therapies, including catheter-based interventions for patients with more severe PE, has become progressively daunting. Accordingly, clinicians frequently turn to evidence-based clinical practice guidelines for diagnostic and management recommendations. However, numerous international guidelines, heterogeneity in recommendations, as well as areas of uncertainty or omission may leave the readers and clinicians without a clear management pathway. In this review of international PE guidelines, we highlight key areas of consistency, difference, and lack of recommendations (silence) with an emphasis on critical clinical and research needs.

Innovation in Catheter-Directed Therapy for Intermediate-High-Risk and High-Risk Pulmonary Embolism.

Although anticoagulation remains the cornerstone treatment for patients with acute pulmonary embolism (PE), catheter-directed therapy (CDT) has generated great interest as an adjunctive option for those presenting with hemodynamic decompensation or high risk for deterioration and in whom systemic thrombolysis has failed or is contraindicated. However, randomized controlled data supporting the efficacy and safety of CDT in addition to antithrombotic therapy in patients with high-risk and intermediate- to high-risk PE compared with anticoagulation and systemic thrombolysis alone are lacking. This paucity of high-quality data hampers guideline recommendations regarding the optimal therapeutic approach in such patients with PE. The aim of the present paper is to critically appraise the current evidence for CDT in patients with high-risk and intermediate- to high-risk PE and to highlight major areas of innovation in the recent literature. In addition, the authors describe unmet clinical and research needs, potential strategies to resolve these knowledge gaps, and pathways for device selection.

Pharmacokinetic and Pharmacodynamic Interactions between Food or Herbal Products and Oral Anticoagulants: Evidence Review, Practical Recommendations, and Knowledge Gaps.

Interactions between food and oral anticoagulants (OACs), particularly vitamin K antagonists such as warfarin, are widely recognized and may also be clinically relevant for direct OACs. Pharmacokinetic and pharmacodynamic interactions with food or herbs can lead to anticoagulation potentiation, increased risk of bleeding, or reduced drug efficacy, all compromising patient safety. We conducted a systematic search for randomized controlled trials (RCTs) on PubMed for assessments of interactions between OACs and various ingestants. Since the RCT evidence was slim, we also reviewed prospective longitudinal studies, case series, and case reports to identify possible associations between foods and anticoagulation therapy. We referred to basic or translational studies that shared putative explanations for such interactions, but we failed to identify high-quality evidence in most cases. The limited evidence, small sample size of the studies, conflicting results, and possible heterogeneity in the contents of herbal products prevent a conclusive assessment of these interactions. Existing evidence suggests that (1) cranberry juice consumption (up to 240 mL/d and probably even more) with warfarin is safe; (2) use of green leafy vegetables with a high daily content (more than 250 µg) of vitamin K should be cautioned for patients receiving warfarin, because it may decrease warfarin efficacy. It is also advisable for patients to maintain highly constant intake of green leafy vegetables to ensure stable warfarin effectiveness; (3) ginger, even in small quantities (excluding commercial ginger-flavored beverages, which contain only negligible amounts of ginger), and mango (more than one fruit) can both potentiate warfarin effects; (4) patients taking OACs should avoid St. John's wort due to diminished anticoagulant effect; and (5) consumption of less than 240 mL of grapefruit juice daily is unlikely to interact with OACs. Future longitudinal observational cohort studies and RCTs with larger sample sizes are needed to study specific interactions between food or herbal products and OACs.

Pulmonary hypertension-related deaths in patients with acute pulmonary embolism in the United States, 2003 to 2020.

BACKGROUND: Data regarding the mortality trends in pulmonary embolism (PE)-related mortality in patients with concomitant pulmonary hypertension (PH) are lacking. We assessed the trends in PE-related mortality in patients with concomitant PH in the United States (US) over the past 2 decades and during the first year of the COVID-19 pandemic using data from the Centers for Disease Control and Prevention's (CDC) Wide-ranging ONline Data for Epidemiologic Research (WONDER) dataset. METHODS: Mortality data were retrieved from the publicly available CDC WONDER mortality dataset from 2003 to 2020. Age-adjusted mortality rates (AAMRs), per 100,000 population, were assessed using Joinpoint regression modelling and expressed as estimated average annual percentage change (AAPC) with relative 95% CIs and stratified by urbanicity, sex, age, and race/ethnicity. RESULTS: Over the study period, the AAMR for PE/PH-related mortality linearly increased (AAPC: +4.3% [95% CI: 3.7 to 4.9], p < 0.001) without sex differences. The AAMR increase was more pronounced in White individuals (AAPC: +4.8% [95% CI: 4.1 to 5.5], p < 0.001) and in subjects living in rural areas (AAPC: +5.1% [95% CI: 3.8 to 6.4], p < 0.001) compared to those living in urban areas. During the first year of the COVID-19 pandemic there was a significant excess in PE/PH-related mortality among women, older than 65 years and living in rural areas. CONCLUSIONS: The rate of PE/PH-related mortality in the US is increasing. Although the early diagnosis of PH in patients with acute PE has become easier with improved diagnostic modalities, the mortality rate of these patients remains high.

Acute Pulmonary Embolism: Evidence, Innovation, and Horizons.

PURPOSE OF REVIEW: Pulmonary embolism (PE) is the third most common cause of cardiovascular morbidity and mortality. The goal of this review is to discuss the most up-to-date literature on epidemiology, diagnosis, risk stratification, and management of acute PE. RECENT FINDINGS: Despite an increase in annual incidence rate of PE in the United States and development of multiple advanced therapies for treatment of acute PE, PE-related mortality is not consistently decreasing across populations. Although multiple risk stratification schemes have been developed, it is still unclear which advanced therapy should be used for the individual patient and optimal timing. Fortunately, multiple randomized clinical trials are underway to answer these questions. Nevertheless, up to 50% of patients have persistent reduced quality of life 6 months after acute PE, termed post-PE syndrome. Despite advances in therapeutic options for management of acute PE, many questions remain unanswered, including optimal risk stratification and management of acute PE.

Extracorporeal Membrane Oxygenation and Reperfusion Strategies in High-Risk Pulmonary Embolism Hospitalizations.

OBJECTIVES: To investigate the contemporary use of extracorporeal membrane oxygenation (ECMO) in conjunction with reperfusion strategies in high-risk pulmonary embolism (PE). DESIGN: Observational epidemiological analysis. SETTING: The U.S. Nationwide Inpatient Sample (NIS) (years 2016-2020). PATIENTS: High-risk PE hospitalizations. MEASUREMENTS AND MAIN RESULTS: Use of ECMO in conjunction with thrombolysis-based reperfusion (systemic thrombolysis or catheter-directed thrombolysis) or mechanical reperfusion (surgical embolectomy or catheter-based thrombectomy) with regards to in-hospital mortality and major bleeding. We identified high-risk PE hospitalizations in the NIS (years 2016-2020) and investigated the use of ECMO in conjunction with thrombolysis-based (systemic thrombolysis or catheter-directed thrombolysis) and mechanical (surgical embolectomy or catheter-based thrombectomy) reperfusion strategies with regards to in-hospital mortality and major bleeding. Among 122,735 hospitalizations for high-risk PE, ECMO was used in 2,805 (2.3%); stand-alone in 1.4%, thrombolysis-based reperfusion in 0.4%, and mechanical reperfusion in 0.5%. Compared with neither reperfusion nor ECMO, ECMO plus thrombolysis-based reperfusion was associated with reduced in-hospital mortality (adjusted odds ratio [aOR] 0.61; 95% CI, 0.38-0.98), whereas no difference was found with ECMO plus mechanical reperfusion (aOR 1.03; 95% CI, 0.67-1.60), and ECMO stand-alone was associated with increased in-hospital mortality (aOR 1.60; 95% CI, 1.22-2.10). In the cardiac arrest subgroup, ECMO was associated with reduced in-hospital mortality (aOR 0.71; 95% CI, 0.53-0.93). Among all patients on ECMO, thrombolysis-based reperfusion was significantly associated (aOR 0.55; 95% CI, 0.33-0.91), and mechanical reperfusion showed a trend (aOR 0.75; 95% CI, 0.47-1.19) toward reduced in-hospital mortality compared with no reperfusion, without increases in major bleeding. CONCLUSIONS: In patients with high-risk PE and refractory hemodynamic instability, ECMO may be a valuable supportive treatment in conjunction with reperfusion treatment but not as a stand-alone treatment especially for patients suffering from cardiac arrest.

Direct oral anticoagulants for treatment of venous thrombosis: illustrated review of appropriate use.

Direct oral anticoagulants (DOACs) have become the preferred option for treatment of venous thromboembolism due to their favorable profile compared with other agents such as vitamin K antagonists or low-molecular-weight heparin. However, findings from randomized controlled trials suggest efficacy and/or safety concerns with DOAC use in some clinical contexts. This illustrated review will summarize indications where DOACs have proven efficacy and safety, situations where they fall short, and situations where uncertainty remains compared with other treatments for venous thromboembolism.

Optimal hemodynamic parameters for risk stratification in acute pulmonary embolism patients.

Hemodynamic assessment of patients with pulmonary embolism (PE) remains a fundamental component of early risk stratification that in turn, influences subsequent monitoring and therapeutic strategies. The current body of literature and international evidence-based clinical practice guidelines focus mainly on the use of systolic blood pressure (SBP). The accuracy of this single hemodynamic parameter, however, and its optimal values for the identification of hemodynamic instability have been recently questioned by clinicians. For example, abnormal SBP or shock index may be a late indicator of adverse outcomes, signaling a patient in whom the cascade of hemodynamic compromise is already well underway. The aim of the present article is to review the current evidence supporting the use of SBP and analyze the potential integration of other parameters to assess the hemodynamic stability, impending clinical deterioration, and guide the reperfusion treatment in patients with PE, as well as to suggest potential strategies to further investigate this issue.

Cardiovascular Risk in Young Patients Diagnosed With Obstructive Sleep Apnea.

BACKGROUND: In older adults, obstructive sleep apnea (OSA) has been associated with several cardiovascular complications. Whether young patients diagnosed with OSA also are at higher risk of developing subsequent cardiovascular disease is uncertain. We aimed to estimate the risk of developing an incident cardiovascular event among young patients diagnosed with OSA. METHODS AND RESULTS: We linked nationwide Danish health registries to identify a cohort of patients aged ≤50 years with OSA using data from 2010 through 2018. Cases without OSA from the general population were matched as controls (1:5). The main outcome was any cardiovascular event (including hypertension, diabetes, atrial fibrillation, ischemic heart disease, ischemic stroke, heart failure, and venous thromboembolism). All-cause mortality was a secondary outcome. The study included 20 240 patients aged ≤50 years with OSA (19.6% female; mean±SD age 39.9±7.7 years) and 80 314 controls. After 5-year follow-up, 31.8% of the patients with OSA developed any cardiovascular event compared with 16.5% of the controls, with a corresponding relative risk (RR) of 1.96 (95% CI, 1.90-2.02). At 5-year follow-up, 27.3% of patients with OSA developed incident hypertension compared with 15.0% of the controls (RR, 1.84 [95% CI, 1.78-1.90]). Incident diabetes occurred in 6.8% of the patients with OSA and 1.4% of controls (RR, 5.05 [95% CI, 4.60-5.54]). CONCLUSIONS: Similar to older adults, young adults with OSA demonstrate increased risk of developing cardiovascular events. To prevent cardiovascular disease progression, accumulation of cardiovascular risk factors, and mortality, risk stratification and prevention strategies should be considered for these patients.

Low absolute risk of thrombotic and cardiovascular events in outpatient pregnant women with COVID-19.

INTRODUCTION: Pregnancy may contribute to an excess risk of thrombotic or cardiovascular events. COVID-19 increases the risk of these events, although the risk is relatively limited among outpatients. We sought to determine whether outpatient pregnant women with COVID-19 are at a high risk for cardiovascular or thrombotic events. MATERIALS & METHODS: We analyzed pregnant outpatients with COVID-19 from the multicenter CORONA-VTE-Network registry. The main study outcomes were a composite of adjudicated venous or arterial thrombotic events, and a composite of adjudicated cardiovascular events. Events were assessed 90 days after the COVID-19 diagnosis and reported for non-pregnant women ≤45 years, and for men ≤45 years, as points of reference. RESULTS: Among 6585 outpatients, 169 were pregnant at diagnosis. By 90-day follow-up, two pregnant women during the third trimester had lower extremity venous thrombosis, one deep and one superficial vein thrombosis. The cumulative incidence of thrombotic events was 1.20 % (95 % confidence interval [CI]: 0.0 to 2.84 %). Respective rates were 0.47 % (95 % CI: 0.14 % to 0.79 %) among non-pregnant women, and 0.49 % (95 % CI: 0.06 % to 0.91 %) among men ≤45 years. No non-thrombotic cardiovascular events occurred in pregnant women. The rates of cardiovascular events were 0.53 % (95 % CI: 0.18 to 0.87) among non-pregnant women, and 0.68 % (95 % CI: 0.18 to 1.18) in men aged ≤45 years. CONCLUSIONS: Thrombotic and cardiovascular events are rare among outpatients with COVID-19. Although a higher event rate among outpatient pregnant women cannot be excluded, the absolute event rates are low and do not warrant population-wide cardiovascular interventions to optimize outcomes.

Fibrinolytic Agents in Thromboembolic Diseases: Historical Perspectives and Approved Indications.

Fibrinolytic agents catalyze the conversion of the inactive proenzyme plasminogen into the active protease plasmin, degrading fibrin within the thrombus and recanalizing occluded vessels. The history of these medications dates to the discovery of the first fibrinolytic compound, streptokinase, from bacterial cultures in 1933. Over time, researchers identified two other plasminogen activators in human samples, namely urokinase and tissue plasminogen activator (tPA). Subsequently, tPA was cloned using recombinant DNA methods to produce alteplase. Several additional derivatives of tPA, such as tenecteplase and reteplase, were developed to extend the plasma half-life of tPA. Over the past decades, fibrinolytic medications have been widely used to manage patients with venous and arterial thromboembolic events. Currently, alteplase is approved by the U.S. Food and Drug Administration (FDA) for use in patients with pulmonary embolism with hemodynamic compromise, ST-segment elevation myocardial infarction (STEMI), acute ischemic stroke, and central venous access device occlusion. Reteplase and tenecteplase have also received FDA approval for treating patients with STEMI. This review provides an overview of the historical background related to fibrinolytic agents and briefly summarizes their approved indications across various thromboembolic diseases.

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

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

Prospective Multicenter International Registry of Ultrasound-Facilitated Catheter-Directed Thrombolysis in Intermediate-High and High-Risk Pulmonary Embolism (KNOCOUT PE).

BACKGROUND: Prior clinical trials have demonstrated the efficacy of ultrasound-facilitated catheter-directed thrombolysis (USCDT) for the treatment of acute intermediate-risk pulmonary embolism (PE) using reduced thrombolytic doses and shorter infusion durations. However, utilization and safety of such strategies in broader PE populations remain unclear. The KNOCOUT PE (The EKoSoNic Registry of the Treatment and Clinical Outcomes of Patients With Pulmonary Embolism) registry is a multicenter international registry designed to study the treatment of acute PE with USCDT, with focus on safety outcomes. METHODS: The KNOCOUT PE prospective cohort included 489 patients (64 sites internationally) with acute intermediate-high or high-risk PE treated with USCDT between March 2018 and June 2020. Principal safety outcomes were independently adjudicated International Society on Thrombosis and Haemostasis major bleeding at 72 hours post-treatment and mortality within 12 months of treatment. Additional outcomes included change in right ventricular/left ventricular ratio and quality of life measures over 12 months. RESULTS: Mean alteplase (r-tPA [recombinant tissue-type plasminogen activator]) infusion duration was 10.5 hours. Mean total r-tPA dose was 18.1 mg, with 31.0% of patients receiving ≤12 mg. Major bleeding events within 72 hours occurred in 1.6% (8/489) of patients. One patient experienced worsening of a preexisting subdural hematoma after USCDT and therapeutic anticoagulation, which ultimately required surgery. All-cause mortality at 30 days was 1.0% (5/489). Improvement in PE quality of life score was observed with a 41.1% (243/489, 49.7%) and 44.2% (153/489, 31.3%) mean relative reduction by 3 and 12 months, respectively. CONCLUSIONS: In a prospective observational cohort study of patients with intermediate-high and high-risk PE undergoing USCDT, mean r-tPA dose was 18 mg, and the rates of major bleeding and mortality were low. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03426124.

External validation of the PE-SARD risk score for predicting early bleeding in acute pulmonary embolism in the RIETE Registry.

INTRODUCTION: The PE-SARD score (syncope, anemia, renal dysfunction) was developed to predict the risk of major bleeding in the acute phase of pulmonary embolism (PE). METHODS: We analyzed data from 50,686 patients with acute PE included in the RIETE registry to externally validate the PE-SARD score. We calculated the overall reliability of the PE-SARD score, as well as discrimination and calibration for predicting the risk of major bleeding at 30 days. The performance of PE-SARD was compared to the BACS and PE-CH models. RESULTS: During the first 30 days, 640 patients (1.3 %) had a major bleeding event. The incidence of major bleeding within 30 days was 0.6 % in the PE-SARD-defined low-risk group, 1.5 % in the intermediate-risk group, and 2.5 % in the high-risk group, for an OR of 2.22 (95 % CI, 2.02-2.43) for the intermediate-risk group (vs low-risk group), and 3.94 for the high-risk group (vs low-risk group). The corresponding sensitivity was 81.1 % (intermediate/high vs low risk), and specificity was 85.9 % (95 % CI, 85.8-86.1) (low/intermediate vs high risk). The applicability of PE-SARD was consistent across clinically relevant patient subgroups and over shorter time periods of follow-up (i.e., 3 and 7 days). The C-index was 0.654 and calibration was excellent. The PE-SARD bleeding score improved the major bleeding risk prediction compared with the BACS and PE-CH scores. CONCLUSIONS: The PE-SARD score identifies PE patients with a higher risk of bleeding, which could assist providers for potentially adjusting PE management, in a framework of shared decision-making with individual patients.

Trends of Pulmonary Embolism-Related Sudden Cardiac Death in the United States, 1999-2019.

OBJECTIVES: Up-to-date population-based data on pulmonary embolism (PE)-related sudden cardiac death (SCD) mortality trends in the United States (US) are scant. We assess the current trends in PE-related SCD mortality in US over the past two decades and determine differences by sex, race, ethnicity, age, and census region. METHODS: We extracted PE-related SCD mortality rates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database from 1999 to 2019, in patients aged ≥ 15 years old. Age-adjusted mortality rates (AAMRs) were assessed using the Joinpoint regression modeling and expressed as estimated average annual percentage change (AAPC) with relative 95% confidence intervals (CIs). RESULTS: Between 1999 and 2019, the AAMR from acute PE-related SCD mortality in the US linearly increased [AAPC: +2.4% (95% CI: 2.2 to 2.6), p < 0.001)]. The AAMR increase was more pronounced in men [AAPC: +2.8% (95% CI: 2.6 to 2.9), p < 0.001], Whites [AAPC: +2.7% (95% CI: 2.3 to 3.1), p < 0.001], Latinx/Hispanic patients [AAPC:+2.0% (95% CI: 1.2 to 2.8), p < 0.001], subjects younger than 65 years [AAPC: +2.4% (95% CI: 2.1 to 2.6), p < 0.001] and in residents of rural areas [AAPC: +3.6% (95% CI: 3.3 to 3.9), p < 0.001]. Moreover, higher percentages of PE-related SCD and the relative absolute number of deaths were observed in the South compared with other geographical regions. CONCLUSIONS: PE-related SCD mortality in the US has increased over the last two decades. Stratification by race, ethnicity, urbanization, and census region demonstrates ethnoracial and regional disparities that require further investigation and remedy.