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.

Developmental or Procedural Vena Cava Interruption and Venous Thromboembolism: A Review.

The inferior vena cava (IVC) and superior vena cava are the main conduits of the systemic venous circulation into the right atrium. Developmental or procedural interruptions of vena cava might predispose to stasis and deep vein thrombosis (DVT) distal to the anomaly and may impact the subsequent rate of pulmonary embolism (PE). This study aimed to review the various etiologies of developmental or procedural vena cava interruption and their impact on venous thromboembolism. A systematic search was performed in PubMed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines per each clinical question. For management questions with no high-quality evidence and no mutual agreements between authors, Delphi methods were used. IVC agenesis is the most common form of congenital vena cava interruption, is associated with an increased risk of DVT, and should be suspected in young patients with unexpected extensive bilateral DVT. Surgical techniques for vena cava interruption (ligation, clipping, and plication) to prevent PE have been largely abandoned due to short-term procedural risks and long-term complications, although survivors of prior procedures are occasionally encountered. Vena cava filters are now the most commonly used method of procedural interruption, frequently placed in the infrarenal IVC. The most agreed-upon indication for vena cava filters is for patients with acute venous thromboembolism and coexisting contraindications to anticoagulation. Familiarity with different forms of vena cava interruption and their local and systemic adverse effects is important to minimize complications and thrombotic events.

Community Socioeconomic Status, Acute Cardiovascular Hospitalizations, and Mortality in Medicare, 2003 to 2019.

BACKGROUND: Socioeconomically disadvantaged communities in the United States disproportionately experience poor cardiovascular outcomes. Little is known about how hospitalizations and mortality for acute cardiovascular conditions have changed among Medicare beneficiaries in socioeconomically disadvantaged and nondisadvantaged communities over the past 2 decades. METHODS: Medicare files were linked with the Centers for Disease Control and Prevention's social vulnerability index to examine age-sex standardized hospitalizations for myocardial infarction, heart failure, ischemic stroke, and pulmonary embolism among Medicare fee-for-service beneficiaries ≥65 years of age residing in socioeconomically disadvantaged communities (highest social vulnerability index quintile nationally) and nondisadvantaged communities (all other quintiles) from 2003 to 2019, as well as risk-adjusted 30-day mortality among hospitalized beneficiaries. RESULTS: A total of 10 942 483 Medicare beneficiaries ≥65 years of age were hospitalized for myocardial infarction, heart failure, stroke, or pulmonary embolism (mean age, 79.2 [SD, 8.7] years; 53.9% female). Although age-sex standardized myocardial infarction hospitalizations declined in socioeconomically disadvantaged (990-650 per 100 000) and nondisadvantaged communities (950-570 per 100 000) from 2003 to 2019, the gap in hospitalizations between these groups significantly widened (adjusted odds ratio 2003, 1.03 [95% CI, 1.02-1.04]; adjusted odds ratio 2019, 1.14 [95% CI, 1.13-1.16]). There was a similar decline in hospitalizations for heart failure in socioeconomically disadvantaged (2063-1559 per 100 000) and nondisadvantaged communities (1767-1385 per 100 000), as well as for ischemic stroke, but the relative gap did not change for both conditions. In contrast, pulmonary embolism hospitalizations increased in both disadvantaged (146-184 per 100 000) and nondisadvantaged communities (153-184 per 100 000). By 2019, risk-adjusted 30-day mortality was similar between hospitalized beneficiaries from socioeconomically disadvantaged and nondisadvantaged communities for myocardial infarction, heart failure, and ischemic stroke but was higher for pulmonary embolism (odds ratio, 1.10 [95% CI, 1.01-1.20]). CONCLUSIONS: Over the past 2 decades, hospitalizations for most acute cardiovascular conditions decreased in both socioeconomically disadvantaged and nondisadvantaged communities, although significant disparities remain, while 30-day mortality is now similar across most conditions.

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.

When Direct Oral Anticoagulants Should Not Be Standard Treatment: JACC State-of-the-Art Review.

For most patients, direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prevention in atrial fibrillation and for venous thromboembolism treatment. However, randomized controlled trials suggest that DOACs may not be as efficacious or as safe as the current standard of care in conditions such as mechanical heart valves, thrombotic antiphospholipid syndrome, and atrial fibrillation associated with rheumatic heart disease. DOACs do not provide a net benefit in conditions such as embolic stroke of undetermined source. Their efficacy is uncertain for conditions such as left ventricular thrombus, catheter-associated deep vein thrombosis, cerebral venous sinus thrombosis, and for patients with atrial fibrillation or venous thrombosis who have end-stage renal disease. This paper provides an evidence-based review of randomized controlled trials on DOACs, detailing when they have demonstrated efficacy and safety, when DOACs should not be the standard of care, where their safety and efficacy are uncertain, and areas requiring further research.

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.

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.

Destaques do VII international symposium of thrombosis and anticoagulation (ISTA) / Highlights of VII international symposium of thrombosis and anticoagulation (ISTA)

O VII Simpósio Internacional de Trombose e Anticoagulação (ISTA) foi realizado em São Paulo, SP, Brasil, nos dias 24 e 25 de outubro de 2014, tendo como principais propósitos a discussão e o compartilhamento de conhecimentos sobre os avanços recentes na abordagem diagnóstica e terapêutica de pacientes com distúrbios trombóticos, nas suas diversas formas de apresentação clínica. O programa científico deste simpósio foi cuidadosamente desenvolvido por líderes de três importantes institutos de pesquisa clínica: o Instituto Brasileiro de Pesquisa Clínica(BCRI), o Duke Clinical Research Institute (DCRI), e Instituto de Pesquisa do Hospital do Coração. Composto por dois dias de apresentações acadêmicas e discussão aberta, o simpósio teve como principal objetivo educar, motivar e inspirar os clínicos, cardiologistas, hematologistas, e outros médicos através de apresentações e discussões de aspectos práticos de condutas que envolvem síndromes relacionadas à trombose e suas respectivas terapias antitrombóticas. Estas atividades possibilitaram uma interação direta entre a plateia e o corpo de palestrantes, composto por médicos de grande experiência clínica e pelos médicos pesquisadores que desenvolveram os principais estudos publicados que guiam nossas condutas em situações relacionadas ao tema "trombose e anticoagulação". Este artigo resume os anais deste simpósio.

The VII International Symposium on Thrombosis and Anticoagulation (ISTA) was held in São Paulo, Brazil, on 24 and 25 October 2014, with the main objectives to discuss and share knowledge on recent advances in the diagnosis and management of patients with thrombotic disorders. The scientific program of this symposium was carefully developed by leaders of three major clinical research institutes: the Brazilian Institute of Clinical Research (BCRI), the Duke Clinical Research Institute from Duke University, and the Research Institute from Hospital do Coração. Comprising two days of academic presentations and open discussion, the symposium aimed to educate, motivate and inspire clinicians, cardiologists, hematologists, and other doctors through presentations and discussions of practical aspects in themes related to thrombosis and anticoagulation. These activities were presented by physicians of great clinical experience and who participated in the main publications that guide our approach on situations related to the theme "thrombosis and anticoagulation". This article summarizes the proceedings of this symposium.