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.

Outcomes of catheter-directed thrombolysis vs. standard medical therapy in patients with acute submassive pulmonary embolism.

BACKGROUND: Catheter-directed thrombolysis (CDL) is increasingly being used for the treatment of submassive and massive pulmonary embolism. Although this therapy has been shown to be effective at reducing right ventricle strain, the impact on clinical outcomes remains unclear. We therefore aimed to evaluate the outcomes of CDL compared to standard anticoagulation for submassive pulmonary embolism patients in a large cohort. METHODS: We conducted a retrospective observational study of consecutive patients with a primary diagnosis of submassive pulmonary embolism admitted to an intensive care unit within our health system between June 2014 and April 2016. We compared the outcome of patients treated with systemic anticoagulation (medical therapy) vs. catheter-based delivery of tissue plasminogen activator (tPA) (CDL). CDL patients were matched with medical therapy controls using a propensity-score matching algorithm based on the components of the simplified pulmonary embolism severity index (sPESI) score. RESULTS: Unadjusted mortality rates were 3.0% for CDL vs. 10.4% for medical therapy at 30 days and 8.1% for CDL vs. 22.9% for medical therapy at 1 year. In the propensity-score matched cohort, mortality rates were 3.1% for CDL vs. 6.1% for medical therapy at 30 days and 8.2% for CDL vs. 18.2% for medical therapy at 1 year. Length of stay was significantly shorter in the CDL group. The index admission bleeding and transfusion rates were not increased in the CDL group. CONCLUSIONS: In patients presenting with acute submassive pulmonary embolism who are admitted to an intensive care unit, the group treated with CDL experienced reduced mortality at 30 days and 1 year when compared to medical therapy without increase in bleeding. Further randomized studies are required to confirm these findings.

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

OBJECTIVES: 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). BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial.

OBJECTIVES: The aim of this study was to determine the lowest optimal tissue plasminogen activator (tPA) dose and delivery duration using ultrasound-facilitated catheter-directed thrombolysis (USCDT) for the treatment of acute intermediate-risk (submassive) pulmonary embolism. BACKGROUND: Previous trials of USCDT used tPA over 12 to 24 h at doses of 20 to 24 mg for acute pulmonary embolism. METHODS: Hemodynamically stable adults with acute intermediate-risk pulmonary embolism documented by computed tomographic angiography were randomized into this prospective multicenter, parallel-group trial. Patients received treatment with 1 of 4 USCDT regimens. The tPA dose ranged from 4 to 12 mg per lung and infusion duration from 2 to 6 h. The primary efficacy endpoint was reduction in right ventricular-to-left ventricular diameter ratio by computed tomographic angiography. A major secondary endpoint was embolic burden by refined modified Miller score, measured on computed tomographic angiography 48 h after initiation of USCDT. RESULTS: One hundred one patients were randomized, and improvements in right ventricular-to-left ventricular diameter ratio were as follows: arm 1 (4 mg/lung/2 h), 0.40 (24%; p = 0.0001); arm 2 (4 mg/lung/4 h), 0.35 (22.6%; p = 0.0001); arm 3 (6 mg/lung/6 h), 0.42 (26.3%; p = 0.0001); and arm 4 (12 mg/lung/6 h), 0.48 (25.5%; p = 0.0001). Improvement in refined modified Miller score was also seen in all groups. Four patients experienced major bleeding (4%). Of 2 intracranial hemorrhage events, 1 was attributed to tPA delivered by USCDT. CONCLUSIONS: Treatment with USCDT using a shorter delivery duration and lower-dose tPA was associated with improved right ventricular function and reduced clot burden compared with baseline. The major bleeding rate was low, but 1 intracranial hemorrhage event due to tPA delivered by USCDT did occur.

Catheter-directed interventions compared with systemic thrombolysis achieve improved ventricular function recovery at a potentially lower complication rate for acute pulmonary embolism.

OBJECTIVE: Catheter-directed interventions (CDIs) are increasingly performed for acute pulmonary embolism (PE) as they are presumed to provide similar therapeutic benefits to systemic thrombolysis (ST) while decreasing the associated complications. The purpose of this study was to compare outcomes between CDI and ST. METHODS: Consecutive patients who underwent CDIs or ST for massive or submassive PE between 2006 and 2016 were identified. Clinical and echocardiographic parameters at baseline and after treatment were recorded. Clinical success was defined as decompensation resolution (or prevention) without major bleeding, stroke, other major treatment-related event, or in-hospital death. The χ2 test and t-test were used for between-groups comparisons. RESULTS: There were 213 patients who received CDIs (standard catheter thrombolysis in 56, ultrasound-assisted thrombolysis in 146, suction thrombectomies in 10, and pharmacomechanical thrombolysis in 1) and 104 patients who received ST (94 high dose [100 mg], 10 low dose [50 mg]). At baseline, CDI and ST groups had comparable echocardiographic parameters, demographics, and comorbidities, except for PE type (massive PE, 8.5% for CDIs vs 69.2% for ST; P < .001), age (60.2 ± 14.9 years for CDIs vs 55.9 ± 17.3 years for ST; P = .023), and renal function (glomerular filtration rate, 78.1 ± 33.7 mL/min/1.73 m2 for CDIs vs 64.1 ± 35.2 mL/min/1.73 m2 for ST; P = .001). Without stratifying per PE type, CDIs had a higher clinical success rate (87.8% vs 66.3%; P < .001) and a lower rate of major bleed (8.0% vs 19.2%; P = .003), stroke (1.4% vs 4.8%; P = .120), and death (1.4% vs 13.5%; P < .001). On stratifying by PE type, there was no difference in clinical success between groups. The mean reduction in right ventricular/left ventricular diameter ratio between baseline and the first post-treatment echocardiographic examination (within 30 days) was significantly higher for CDI (0.27 ± 0.20 vs 0.18 ± 0.15; P = .037). Beyond 30 days, there was no echocardiographic difference between groups. There was no significant difference in clinical outcomes and echocardiographic parameters between standard and ultrasound-assisted CDIs. CONCLUSIONS: CDIs provide improved recovery of right ventricular function compared with ST. Major bleeding and stroke complications may be lower, but larger studies are needed to validate this. CDIs are complementary to ST, and their use should be individualized on the basis of the patients' clinical presentation, risk profile, and local resources.