Background:The relationship between the early hemodynamic consequences of acute pulmonary embolism (PE) and short-term morbidity and mortality has long been recognized. The mortality incidence and other complications after high-risk (massive) PE, the most severe category of the disease, are summarized in this meta-analysis. Methods:A systematic review and meta-analysis of studies reporting on patients with massive PE indexed by PubMed and the Cochrane Library over a 10-year period (2010-2020) was conducted. Studies with adequate information to specify a cohort of patients with high-risk PE defined by the American Heart Association and European Society of Cardiology criteria and their clinical outcomes were included. Incidences were calculated as weighted averages with 95% CIs. Results:A total of 27 publications spanning 1517 patients were identified that met the search criteria for high-risk PE. In-hospital all-cause mortality averaged 28.3% (95% CI, 20.9%-37.0%) in patients at high risk, comparable to the 30-day all-cause mortality of 30.2% (95% CI, 22.3%-39.6%). In-hospital major bleeding was 13.8% (95% CI, 9.3%-20.0%), and intracranial hemorrhage was reported in 3.6% (95% CI, 2.2%-5.9%). The risk of bias in publications was graded as low-to-moderate, with substantial heterogeneity among the studies. Conclusions:This systematic review and meta-analysis provided low-quality to moderate-quality evidence documenting mortality, major bleeding, and other complications in patients meeting the American Heart Association and European Society of Cardiology criteria for high-risk PE. This information was used to inform the design of the FLowTriever for Acute Massive Pulmonary Embolism (FLAME) study (NCT04795167), a study evaluating an advanced therapy for patients with high-risk PE.

BACKGROUND:The identification of hemodynamically stable pulmonary embolism (PE) patients who may benefit from advanced treatment beyond anticoagulation is unclear. However, when intervention is deemed necessary by the PE patient's care team, data to select the most advantageous interventional treatment option are lacking. Limiting factors include major bleeding risks with systemic and locally delivered thrombolytics and the overall lack of randomized controlled trial (RCT) data for interventional treatment strategies. Considering the expansion of the pulmonary embolism response team (PERT) model, corresponding rise in interventional treatment, and number of thrombolytic and nonthrombolytic catheter-directed devices coming to market, robust evidence is needed to identify the safest and most effective interventional option for patients. METHODS:The PEERLESS study (ClinicalTrials.gov identifier: NCT05111613) is a currently enrolling multinational RCT comparing large-bore mechanical thrombectomy (MT) with the FlowTriever System (Inari Medical, Irvine, CA) vs catheter-directed thrombolysis (CDT). A total of 550 hemodynamically stable PE patients with right ventricular (RV) dysfunction and additional clinical risk factors will undergo 1:1 randomization. Up to 150 additional patients with absolute thrombolytic contraindications may be enrolled into a nonrandomized MT cohort for separate analysis. The primary end point will be assessed at hospital discharge or 7 days post procedure, whichever is sooner, and is a composite of the following clinical outcomes constructed as a hierarchal win ratio: (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to bailout, and (5) intensive care unit admission and length of stay. The first 4 components of the win ratio will be adjudicated by a Clinical Events Committee, and all components will be assessed individually as secondary end points. Other key secondary end points include all-cause mortality and readmission within 30 days of procedure and device- and drug-related serious adverse events through the 30-day visit. IMPLICATIONS:PEERLESS is the first RCT to compare 2 different interventional treatment strategies for hemodynamically stable PE and results will inform strategy selection after the physician or PERT determines advanced therapy is warranted.

Background: Hemodynamically unstable high-risk, or massive, pulmonary embolism (PE) has a reported in-hospital mortality of over 25%. Systemic thrombolysis is the guideline-recommended treatment despite limited evidence. The FLAME study (FlowTriever for Acute Massive PE) was designed to generate evidence for interventional treatments in high-risk PE.Methods: The FLAME study was a prospective, multicenter, nonrandomized, parallel group, observational study of high-risk PE. Eligible patients were treated with FlowTriever mechanical thrombectomy (FlowTriever Arm) or with other contemporary therapies (Context Arm). The primary end point was an in-hospital composite of all-cause mortality, bailout to an alternate thrombus removal strategy, clinical deterioration, and major bleeding. This was compared in the FlowTriever Arm to a prespecified performance goal derived from a contemporary systematic review and meta-analysis.Results: A total of 53 patients were enrolled in the FlowTriever Arm and 61 in the Context Arm. Context Arm patients were primarily treated with systemic thrombolysis (68.9%) or anticoagulation alone (23.0%). The primary end point was reached in 9/53 (17.0%) FlowTriever Arm patients, significantly lower than the 32.0% performance goal (P<0.01). The primary end point was reached in 39/61 (63.9%) Context Arm patients. In-hospital mortality occurred in 1/53 (1.9%) patients in the FlowTriever Arm and in 18/61 (29.5%) patients in the Context Arm.Conclusions: Among patients selected for mechanical thrombectomy with the FlowTriever System, a significantly lower associated rate of in-hospital adverse clinical outcomes was observed compared with a prespecified performance goal, primarily driven by low all-cause mortality of 1.9%.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04795167.

Objective: The aim of the present study was to report a large, single-center experience using the ClotTriever thrombectomy system (Inari Medical, Irvine, CA) for the management of acute iliofemoral (IF) deep vein thrombosis (DVT). One limitation of all endovascular devices for the treatment of acute IF-DVT has been the inability to completely remove all acute thrombus and the need for adjunctive thrombolysis with its attendant risk of bleeding complications. Methods: A single-center retrospective review of consecutive patients with acute IF-DVT treated with the ClotTriever thrombectomy system (Inari Medical) is reported. Procedural efficacy was evaluated by an independent core imaging laboratory (Syntactx, New York, NY). Both procedural and in-hospital safety were assessed during the index hospitalization. The treated vein patency was assessed using duplex ultrasound at 30 days after the procedure. Results: A total of 96 patients were included in the present retrospective review, 40 of whom (40%) had contraindications to thrombolytic therapy. In terms of efficacy, 93 patients (97%) had >= 75% thrombus removal. During the index hospitalization, two patients (2%) had experienced a symptomatic pulmonary embolus. However, no mortality, major bleeding, or device-related complications had occurred in the study population. Of the 96 patients, 64 had undergone duplex ultrasound at 30 days after the procedure. Of the 64 patients, 62 had normal flow (97%), 53 (83%) had normal compressibility, and 11 (17%) had partial compressibility. Conclusions: The ClotTriever thrombectomy catheter was both safe and effective in our cohort of patients with acute IF-DVT outside a randomized clinical trial.

Historically, anticoagulation has been the primary treatment for acute lower extremity deep venous thrombosis (DVT) with or without thrombolysis. Despite large amounts of clinical research data supporting an ‘open vein hypothesis’, which favours early thrombus removal, clinicians have been hesitant to take this option due to a historically high risk of major bleeding and a few notable studies that failed to show any meaningful benefit. The ATTRACT trial failed to show the benefit of using pharmacomechanical catheter-directed thrombolysis (PCDT) for iliofemoral and femoropopliteal DVT but did result in more bleeding. However, the CaVent study before it revealed a significant reduction in post-thrombotic syndrome (PTS) for patients with iliofemoral and femoral DVT after long-term follow-up past 24 months that grew over time. Since these trials, there have been significant advancements in magnetic resonance and CT venography, intravascular ultrasound (IVUS), venous stenting and thrombectomy catheters meaning there is little to no need for adjunct thrombolytics. Results from ongoing research such as CLEAR-DVT reflect the advances in modern technology.

Background Mechanical thrombectomy is increasingly being used as an alternative to pharmacologic therapies for the treatment of patients with acute deep venous thrombosis (DVT) and pulmonary embolism (PE) and allows direct histopathologic comparison of thrombi extracted from living patients. We performed histopathologic analysis to thrombi extracted from cases of DVT and PE to gain insights into their relative cellular compositions. Methods Thrombus retrieved using a catheter-based thrombectomy system (ClotTriever for lower extremity DVT and FlowTriever for PE) from the 17 patients (7 DVT cases and 10 PE cases) were histologically evaluated. Histological features were used to estimate their age and pathological characteristics. Results The thrombus in all cases were composed of fibrin, platelets, red blood cells, and acute inflammatory cells. The weights of thrombus obtained from DVT versus PE cases were heavier (DVT 7.2 g (g) (5.6-10.2) vs. PE 4.8 g (3.6-6.8), p = .01). Overall thrombus healing (i.e., thrombus composed of smooth muscle cells, endothelial cells, and proteoglycans) was different between DVT and PE cases. 6/7 (86%) with features of late stage healing were from DVT cases while only three of ten (30%) were from PE cases while PE contained more acute thrombi with 7/10 (70%) stage 2 as compared 1/7 (14%) for DVT (p = .0498). Conclusion This study is the first to directly compare the histology of extracted thrombus in DVT versus PE cases from patients with clinical events. Overall PE cases demonstrated significantly earlier stage thrombus with a larger component of red blood cells.

The pathogenesis of atherosclerosis is complex, evolves, and involves many cell types. Macrophages and vascular smooth muscle cells (VSMCs) are critically involved in atherosclerosis development and progression. Several studies have shown that WNT5A protein is abundantly expressed in human atherosclerotic lesions; however, the mechanism and role of WNT signaling pathway activation is not clearly known. Using THP-1 derived macrophages, and human aortic VSMC cells, we evaluated in vitro how oxidized low-density lipoprotein (oxLDL) and WNT5A signaling interact in these two cell lines. We used western blot, scratch assay, metabolic proliferation assay, as well as immunostaining to analyze the effect of Wnt signaling activation. The results demonstrated that oxLDL, as well as WNT5A (control), induced Disheveled-2 (DVL2) activation and Kif26b degradation, indicating activation of non-canonical Wnt signaling. We found that oxLDL and WNT5A induced FZD5-ROR2 co-localization at the cellular membrane in vitro in THP-1 derived macrophages. Box5 (FZD5 receptor antagonist) inhibited oxLDL-induced DVL2/JNK activation secondary to newly secreted WNT protein from THP-1 derived macrophages. We found that WNT3A (canonical Wnt) and WNT5A showed different roles in this VSMC cell line. These findings indicate that WNT5A is upregulated by oxLDL, promotes foam cell formation, and affects VSMC phenotype and migration in these two cell lines. Also, in these cell lines FZD5 signaling seems to be necessary for lipid accumulation and, through this mechanism, WNT5A could modulate foam cell formation. Thus, our results suggest that WNT5A may contribute to the pathogenesis of vascular disease through modulating macrophage and VSMC behavior.

Arterial interventional devices have become smaller over time, primarily to reduce rates of access site complications. With arterial lesions representing relatively small treatment targets, technical success has been maintained despite the miniaturization trend. Venous thromboembolism (VTE), however, represents a different problem and requires a different solution. These clots are much larger, frequently chronic, and wall adherent. Additionally, large-bore venous access has been demonstrated to be safe in multiple interventional, structural, and electrophysiologic procedures.1 Accordingly, Inari Medical purposely developed the FlowTriever Mechanical Thrombectomy System for VTE. The system that included a 20-F Triever20 (T20) aspiration guide catheter was validated in the FLARE trial2 and used in approximately 3,500 cases. The current system introduces the 24-F Triever24 (T24) aspiration guide catheter to increase the venous clot extraction effectiveness. Although other thrombectomy devices commonly used for pulmonary embolism (PE) have been repurposed from devices initially intended for the narrow vessels of the arterial system, the FlowTriever System’s large-bore design targets the specific characteristics of VTE, including large amounts of thrombus of varying age and consistencies within the large vessels of the venous system and pulmonary arteries (PAs).3 So, why does the large-bore design play such a vital role in achieving successful VTE thrombectomy? The Hagen-Poiseuille equation of fluid dynamics states that flow rate is directly proportional to radius to the fourth Christopher M. Huff, MD, FACC, RPVI OhioHealth Heart & Vascular Riverside Methodist Hospital Columbus, Ohio christopher.huff@ohiohealth.com Disclosures: Consultant to Inari Medical and Boston Scientific Corporation.

What are your main take-home points from recent trials such as ATTRACT and CAVA?1,2 Dr. Bashir: The take-home message from the ATTRACT trial has been that pharmacomechanical catheter-directed therapy (PCDT) is not effective in reducing postthrombotic syndrome (PTS) in femoropopliteal deep vein thrombosis (DVT); however, there was a consistent reduction in frequency and severity of moderate to severe PTS and Putting Recent DVT Trial Data Into Context and Practice

Purpose: To report final 2-year outcomes with the Sentry bioconvertible inferior vena cava (IVC) filter in patients requiring temporary protection against pulmonary embolism (PE). Materials and Methods: In a prospective multicenter trial, the Sentry filter was implanted in 129 patients with documented deep vein thrombosis (DVT) and/or PE (67.5%) or who were at temporary risk of developing DVT/PE (32.6%). Patients were monitored and bioconversion status ascertained by radiography, computed tomography (CT), and CT venography through 2 years. Results: The composite primary 6-month endpoint of clinical success was achieved in 97.4% (111/114) of patients. The rate of new symptomatic PE was 0% (n = 126) through 1 year and 2.4% (n = 85) through the second year of follow-up, with 2 new nonfatal cases at 581 and 624 days that were adjudicated as not related to the procedure or device. Two patients (1.6%) developed symptomatic caval thrombosis during the first month and underwent successful interventions without recurrence. No other filter-related symptomatic complications occurred through 2 years. There was no filter tilting, migration, embolization, fracture, or caval perforation and no filter-related deaths through 2 years. Filter bioconversion was successful for 95.7% (110/115) of patients at 6 months, 96.4% (106/110) of patients at 12 months, and 96.5% (82/85) of patients at 24 months. Through 24 months of follow-up, there was no evidence of late-stage IVC obstruction or thrombosis after filter bioconversion or of thrombogenicity associated with retracted filter arms. Conclusions: The Sentry IVC filter provided safe and effective protection against PE, with a high rate of intended bioconversion and a low rate of device-related complications, through 2 years of follow-up.

This review discusses the benefits of a completely percutaneous approach to endovascular aortic aneurysm repair (EVAR), and provides an outline as to how this is performed by a multidisciplinary team of cardiologists and cardiovascular surgeons at a quaternary care community hospital.

Background and aims: Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells. Methods: Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors [frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 Ror2)] in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining. Results: Wnt5a (P<.05), Fz5 (P < 0.1) and Ror2 (P<.01) were significantly expressed in advanced atherosclerotic lesions compared to less advanced lesions (N=10).Wnt5a,Fz5, and Ror2 were expressed in macrophages/foam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptorCD36 (P<.05) but not the lipid efflux receptor ATP-binding cassette transporter (P>.05). rWnt5a also significantly increased lipid accumulation in MP-1 macrophages (P<.05). Furthermore, inhibition of Wnt5a signaling with Boxy prevented lipid accumulation (P<.01) and prevented CD36 up-regulation (P<.01). Conclusions: These results suggest a direct role for Wnt5a signaling in the pathogenesis of atherosclerosis, specifically the accumulation of lipid in macrophages and the formation of foam cells. (C) 2018 Elsevier Inc. All rights reserved

PURPOSE:To prospectively assess the Sentry bioconvertible inferior vena cava (IVC) filter in patients requiring temporary protection against pulmonary embolism (PE). MATERIALS AND METHODS:At 23 sites, 129 patients with documented deep vein thrombosis (DVT) or PE, or at temporary risk of developing DVT or PE, unable to use anticoagulation were enrolled. The primary end point was clinical success, including successful filter deployment, freedom from new symptomatic PE through 60 days before filter bioconversion, and 6-month freedom from filter-related complications. Patients were monitored by means of radiography, computerized tomography (CT), and CT venography to assess filtering configuration through 60 days, filter bioconversion, and incidence of PE and filter-related complications through 12 months. RESULTS:Clinical success was achieved in 111 of 114 evaluable patients (97.4%, 95% confidence interval [CI] 92.5%-99.1%). The rate of freedom from new symptomatic PE through 60 days was 100% (n = 129, 95% CI 97.1%-100.0%), and there were no cases of PE through 12 months for either therapeutic or prophylactic indications. Two patients (1.6%) developed symptomatic caval thrombosis during the first month; neither experienced recurrence after successful interventions. There was no filter tilting, migration, embolization, fracture, or caval perforation by the filter, and no filter-related death through 12 months. Filter bioconversion was successful for 95.7% (110/115) at 6 months and for 96.4% (106/110) at 12 months. CONCLUSIONS:The Sentry IVC filter provided safe and effective protection against PE, with a high rate of intended bioconversion and a low rate of device-related complications, through 12 months of imaging-intense follow-up.

Purpose: To report the final 2-year data on the efficacy and safety of a nitinol retrievable inferior vena cava (IVC) filter for protection against pulmonary embolism (PE).Materials and Methods: This was a prospective multicenter trial of 200 patients with temporary indications for caval filtration who underwent implantation of the Denali IVC filter. After filter placement, all patients were followed for 2 years after placement or 30 days after filter retrieval. The primary endpoints, were technical success of filter implantation in the intended location and Clinical success of filter placement and retrieval. Secondary endpoints were incidence of clinically symptomatic recurrent PE, new or propagating deep vein thrombosis (DVT), and filter-related complications including migration, fracture, penetration, and tilt.Results: Filter placement was technically successful in 199 patients (99.5%). Filters were clinically successful in 190 patients (95%). The rate of PE was 3% (n = 6), with 5 patients having a small subsegmental PE and 1 having a lobar PE. New or worsening DVT was noted in 26 patients (13%). Filter retrieval was attempted 125 times in 124 patients and was technically successful in 121 patients (97.6%). The mean filter dwell time at retrieval was 200,8 days (range, 5-736 d). There were no instances of filter fracture, migration, or tilt greater than 15 degrees at the time of filter retrieval or during follow-up.Conclusions: The Denali IVC filter exhibited high success rates for filter placement and retrieval while maintaining a low complication rate in this clinical trial.

Atherosclerosis (ATH) is a chronic inflammatory disease that involves cascades of signaling events mediated by various effector proteins. Here we sought to determine if the expression of Wnt5a, a secreted glycoprotein, is altered in discrete regions of the arterial plaque.Atherosclerotic plaque tissues from 14 human subjects undergoing elective carotid endarterectomy were used in this study. Immunohistochemistry and laser capture microdissection combined with quantitative real-time PCR were used to determine the expression of Wnt5a and Toll-like receptors (TLRs) in different sections of the arterial lesions. Atherosclerotic serum samples (n = 30) and serum from healthy subjects (n = 16) were quantified for Wnt5a using an enzyme-linked immunosorbent assay (ELISA).The data analysis revealed that Wnt5a transcripts and protein were elevated in advanced arterial lesions relative to less advanced arterial lesions; that Wnt5a expression correlated with the presence of TLR4 and TLR2 transcripts; and that the average amount of Wnt5a protein present in atherosclerotic patient serum was significantly higher compared to healthy controls.This study is the first to provide evidence that the expression of Wnt5a increases as the disease progresses to a more advanced stage, and that this expression is coincident with that of TLR2 and TLR4. In addition, we found that the average Wnt5a levels in the serum of atherosclerotic patients are elevated relative to healthy controls, which is consistent with the hypothesis that Wnt5a plays a role in ATH.

OPINION STATEMENT:Resistant hypertension remains a difficult clinical disease to treat. It is known to place a patient at higher risk for developing significant cardiovascular, renal, and cerebrovascular disease. There is a current surge in research investigating renal denervation as potential treatment for resistant hypertension, as an overactive renal sympathetic system is known to exert an influence on the underlying pathophysiology. Several small studies have been published, with more underway, evaluating multiple different catheter-based systems that utilize radiofrequency ablation or ultrasound wave energy. These studies are showing promising results, with reduction in office blood pressure for the majority of patients. However, it appears that this does not always translate into definitive real-world observational effects. Variability exists in the number of patients that are able to reduce the amount of medication they take for hypertension, with some requiring an increase in medication. As a result, a more intensive screening process has been proposed, evaluating specific key predictors that may translate into a more favorable clinical response to renal denervation. We recommend that individuals with resistant hypertension continue to be optimized medically, adequately screened for secondary causes of hypertension, and that they consider participation in a renal denervation clinical trial to aid in further advancing the field.