Randomized controlled trial of mechanical thrombectomy vs catheter-directed thrombolysis for acute hemodynamically stable pulmonary embolism: Rationale and design of the PEERLESS study.

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. 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. 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.

Gonsalves CF ，Gibson CM ，Stortecky S ，Alvarez RA ，Beam DM ，Horowitz JM ，Silver MJ ，Toma C ，Rundback JH ，Rosenberg SP ，Markovitz CD ，Tu T ，Jaber WA ... -  《-》

PEERLESS II: A Randomized Controlled Trial of Large-Bore Thrombectomy Versus Anticoagulation in Intermediate-Risk Pulmonary Embolism.

Anticoagulation (AC) is the guideline-recommended treatment for intermediate-risk pulmonary embolism (PE); however, it remains unclear whether mechanical thrombectomy provides benefit over AC alone. The PEERLESS II study aims to evaluate outcomes in intermediate-risk PE patients randomized to treatment with large-bore mechanical thrombectomy and AC vs AC alone. PEERLESS II is an international randomized controlled trial enrolling up to 1200 patients with intermediate-risk PE and additional clinical risk factors from up to 100 sites. Treatment is randomized 1:1 to large-bore mechanical thrombectomy with the FlowTriever System (Inari Medical) and AC or AC alone. Outcomes will be evaluated for up to 3 months, with safety events independently adjudicated. The primary end point is a hierarchical composite win ratio of (1) all-cause mortality by 30 days, (2) clinical deterioration (earlier of discharge or 30 days), (3) all-cause hospital readmission by 30 days, (4) bailout therapy (earlier of discharge or 30 days), and (5) Modified Medical Research Council (mMRC) dyspnea score of ≥1 at the 48-hour visit. Secondary end points include all-cause and PE-related mortality (30-day and 90-day), all-cause and PE-related readmission (30-day and 90-day), major bleeding (30-day and 90-day), clinical deterioration (earlier of discharge or 30 days), bailout (earlier of discharge or 30 days), right ventricle-to-left ventricle diameter ratio (48-hour visit), mMRC dyspnea score (48-hour, 1-month, and 3-month visits), quality of life using Pulmonary Embolism Quality of Life and EuroQol-5 Dimensions-5 Levels (1-month and 3-month visits), 6-minute walk distance (1-month visit), and post-PE impairment diagnosis (3-month visit). PEERLESS II will inform the understanding of mechanical thrombectomy treatment for intermediate-risk PE and provide evidence for consideration in future treatment guidelines.

Giri J ，Mahfoud F ，Gebauer B ，Andersen A ，Friedman O ，Gandhi RT ，Jaber WA ，Pereira K ，West FM ... -  《-》

A Prospective, Single-Arm, Multicenter Trial of Catheter-Directed Mechanical Thrombectomy for Intermediate-Risk Acute Pulmonary Embolism: The FLARE Study.

The aim of this study was to evaluate the safety and effectiveness of percutaneous mechanical thrombectomy using the FlowTriever System (Inari Medical, Irvine, California) in a prospective trial of patients with acute intermediate-risk pulmonary embolism (PE). Catheter-directed thrombolysis has been shown to improve right ventricular (RV) function in patients with PE. However, catheter-directed thrombolysis increases bleeding risk and many patients with PE have relative and absolute contraindications to thrombolysis. Patients with symptomatic, computed tomography-documented PE and RV/left ventricular (LV) ratios ≥0.9 were eligible for enrollment. The primary effectiveness endpoint was core laboratory-assessed change in RV/LV ratio. The primary safety endpoint comprised device-related death, major bleeding, treatment-related clinical deterioration, pulmonary vascular injury, or cardiac injury within 48 h of thrombectomy. From April 2016 to October 2017, 106 patients were treated with the FlowTriever System at 18 U.S. sites. Two patients (1.9%) received adjunctive thrombolytics and were analyzed separately. Mean procedural time was 94 min; mean intensive care unit stay was 1.5 days. Forty-three patients (41.3%) did not require any intensive care unit stay. At 48 h post-procedure, average RV/LV ratio reduction was 0.38 (25.1%; p < 0.0001). Four patients (3.8%) experienced 6 major adverse events, with 1 patient (1.0%) experiencing major bleeding. One patient (1.0%) died, of undiagnosed breast cancer, through 30-day follow-up. Percutaneous mechanical thrombectomy with the FlowTriever System appears safe and effective in patients with acute intermediate-risk PE, with significant improvement in RV/LV ratio and minimal major bleeding. Potential advantages include immediate thrombus removal, absence of thrombolytic complications, and reduced need for post-procedural critical care.

Tu T ，Toma C ，Tapson VF ，Adams C ，Jaber WA ，Silver M ，Khandhar S ，Amin R ，Weinberg M ，Engelhardt T ，Hunter M ，Holmes D ，Hoots G ，Hamdalla H ，Maholic RL ，Lilly SM ，Ouriel K ，Rosenfield K ，FLARE Investigators ... -  《-》

Catheter-directed therapies for the treatment of high risk (massive) and intermediate risk (submassive) acute pulmonary embolism.

Acute pulmonary embolism (APE) is a major cause of acute morbidity and mortality. APE results in long-term morbidity in up to 50% of survivors, known as post-pulmonary embolism (post-PE) syndrome.  APE can be classified according to the short-term (30-day) risk of mortality, based on a variety of clinical, imaging and laboratory findings. Most mortality and morbidity is concentrated in high-risk (massive) and intermediate-risk (submassive) APE. The first-line treatment for APE is systemic anticoagulation.  High-risk (massive) APE accounts for less than 10% of APE cases and is a life-threatening medical emergency, requiring immediate reperfusion treatment to prevent death. Systemic thrombolysis is the recommended treatment for high-risk (massive) APE. However, only a minority of the people affected receive systemic thrombolysis, due to comorbidities or the 10% risk of major haemorrhagic side effects. Of those who do receive systemic thrombolysis, 8% do not respond in a timely manner. Surgical pulmonary embolectomy is an alternative reperfusion treatment, but is not widely available.  Intermediate-risk (submassive) APE represents 45% to 65% of APE cases, with a short-term mortality rate of around 3%. Systemic thrombolysis is not recommended for this group, as major haemorrhagic complications outweigh the benefit. However, the people at higher risk within this group have a short-term mortality of around 12%, suggesting that anticoagulation alone is not an adequate treatment. Identification and more aggressive treatment of people at intermediate to high risk, who have a more favourable risk profile for reperfusion treatments, could reduce short-term mortality and potentially reduce post-PE syndrome. Catheter-directed treatments (catheter-directed thrombolysis and catheter embolectomy) are minimally invasive reperfusion treatments for high- and intermediate-risk APE. Catheter-directed treatments can be used either as the primary treatment or as salvage treatment after failure of systemic thrombolysis. Catheter-directed thrombolysis administers 10% to 20% of the systemic thrombolysis dose directly into the thrombus in the lungs, potentially reducing the risks of haemorrhagic side effects. Catheter embolectomy mechanically removes the thrombus without the need for thrombolysis, and may be useful for people with contraindications for thrombolysis.  Currently, the benefits of catheter-based APE treatments compared with existing medical and surgical treatment are unclear despite increasing adoption of catheter treatments by PE response teams. This review examines the evidence for the use of catheter-directed treatments in high- and intermediate-risk APE. This evidence could help guide the optimal treatment strategy for people affected by this common and life-threatening condition. To assess the effects of catheter-directed therapies versus alternative treatments for high-risk (massive) and intermediate-risk (submassive) APE. We used standard, extensive Cochrane search methods. The latest search was 15 March 2022. We included randomised controlled trials (RCTs) of catheter-directed therapies for the treatment of high-risk (massive) and intermediate-risk (submassive) APE. We excluded catheter-directed treatments for non-PE. We applied no restrictions on participant age or on the date, language or publication status of RCTs. We used standard Cochrane methods. The main outcomes were all-cause mortality, treatment-associated major and minor haemorrhage rates based on two established clinical definitions, recurrent APE requiring retreatment or change to a different APE treatment, length of hospital stay, and quality of life. We used GRADE to assess certainty of evidence for each outcome. We identified one RCT (59 participants) of (ultrasound-augmented) catheter-directed thrombolysis for intermediate-risk (submassive) APE. We found no trials of any catheter-directed treatments (thrombectomy or thrombolysis) in people with high-risk (massive) APE or of catheter-based embolectomy in people with intermediate-risk (submassive) APE. The included trial compared ultrasound-augmented catheter-directed thrombolysis with alteplase and systemic heparinisation versus systemic heparinisation alone. In the treatment group, each participant received an infusion of alteplase 10 mg or 20 mg over 15 hours. We identified a high risk of selection and performance bias, low risk of detection and reporting bias, and unclear risk of attrition and other bias. Certainty of evidence was very low because of risk of bias and imprecision.  By 90 days, there was no clear difference in all-cause mortality between the treatment group and control group. A single death occurred in the control group at 20 days after randomisation, but it was unrelated to the treatment or to APE (odds ratio (OR) 0.31, 95% confidence interval (CI) 0.01 to 7.96; 59 participants). By 90 days, there were no episodes of treatment-associated major haemorrhage in either the treatment or control group. There was no clear difference in treatment-associated minor haemorrhage between the treatment and control group by 90 days (OR 3.11, 95% CI 0.30 to 31.79; 59 participants). By 90 days, there were no episodes of recurrent APE requiring retreatment or change to a different APE treatment in the treatment or control group. There was no clear difference in the length of mean total hospital stay between the treatment and control groups. Mean stay was 8.9 (standard deviation (SD) 3.4) days in the treatment group versus 8.6 (SD 3.9) days in the control group (mean difference 0.30, 95% CI -1.57 to 2.17; 59 participants). The included trial did not investigate quality of life measures.  AUTHORS' CONCLUSIONS: There is a lack of evidence to support widespread adoption of catheter-based interventional therapies for APE. We identified one small trial showing no clear differences between ultrasound-augmented catheter-directed thrombolysis with alteplase plus systemic heparinisation versus systemic heparinisation alone in all-cause mortality, major and minor haemorrhage rates, recurrent APE and length of hospital stay. Quality of life was not assessed.  Multiple small retrospective case series, prospective patient registries and single-arm studies suggest potential benefits of catheter-based treatments, but they provide insufficient evidence to recommend this approach over other evidence-based treatments. Researchers should consider clinically relevant primary outcomes (e.g. mortality and exercise tolerance), rather than surrogate markers (e.g. right ventricular to left ventricular (RV:LV) ratio or thrombus burden), which have limited clinical utility. Trials must include a control group to determine if the effects are specific to the treatment.

Harvey JJ ，Huang S ，Uberoi R 《Cochrane Database of Systematic Reviews》

Catheter-directed thrombolysis versus suction thrombectomy in the management of acute pulmonary embolism.

Avgerinos ED ，Abou Ali A ，Toma C ，Wu B ，Saadeddin Z ，McDaniel B ，Al-Khoury G ，Chaer RA ... -  《-》