Advancing the management of acute intermediate-high-risk pulmonary embolism: The enduring legacy of Professor Guy Meyer.

Konstantinides SV ，Sanchez O ，Goldhaber SZ ，Meneveau N ... -  《-》

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.

Sanchez O ，Charles-Nelson A ，Ageno W ，Barco S ，Binder H ，Chatellier G ，Duerschmied D ，Empen K ，Ferreira M ，Girard P ，Huisman MV ，Jiménez D ，Katsahian S ，Kozak M ，Lankeit M ，Meneveau N ，Pruszczyk P ，Petris A ，Righini M ，Rosenkranz S ，Schellong S ，Stefanovic B ，Verhamme P ，de Wit K ，Vicaut E ，Zirlik A ，Konstantinides SV ，Meyer G ，PEITHO-3 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》

Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study.

Due to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation remains the standard of care for patients with intermediate-high-risk pulmonary embolism (PE). The Higher-Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) study (ClinicalTrials.gov Identifier: NCT04790370) is a multinational multicenter randomized controlled parallel-group comparison trial. Patients with: (1) confirmed acute PE; (2) evidence of right ventricular (RV) dysfunction on imaging; (3) a positive cardiac troponin test; and (4) clinical criteria indicating an elevated risk of early death or imminent hemodynamic collapse, will be randomized 1:1 to treatment with a standardized protocol of ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, vs anticoagulation alone. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed PE recurrence, within 7 days of randomization. Further assessments cover, apart from bleeding complications, a broad spectrum of functional and patient-reported outcomes including quality of life indicators, functional status and the utilization of health care resources over a 12-month follow-up period. The trial plans to include 406 patients, but the adaptive design permits a sample size increase depending on the results of the predefined interim analysis. As of May 11, 2022, 27 subjects have been enrolled. The trial is funded by Boston Scientific Corporation and through collaborative research agreements with University of Mainz and The PERT Consortium. Regardless of the outcome, HI-PEITHO will establish the first-line treatment in intermediate-high risk PE patients with imminent hemodynamic collapse. The trial is expected to inform international guidelines and set the standard for evaluation of catheter-directed reperfusion options in the future.

Klok FA ，Piazza G ，Sharp ASP ，Ní Ainle F ，Jaff MR ，Chauhan N ，Patel B ，Barco S ，Goldhaber SZ ，Kucher N ，Lang IM ，Schmidtmann I ，Sterling KM ，Becker D ，Martin N ，Rosenfield K ，Konstantinides SV ... -  《-》

Clinical update on thrombolytic use in pulmonary embolism: A focus on intermediate-risk patients.

Current literature on clinical controversies surrounding the use of thrombolytic agents in patients with intermediate-risk pulmonary embolism (PE) is reviewed. PE is a major cause of morbidity and mortality. When used in conjunction with anticoagulation, thrombolysis has been shown to reduce hemodynamic decompensation in select patients, but thrombolytic therapy is associated with high risks of bleeding and intracranial hemorrhage and its role in treating patients with intermediate-risk PE remains controversial. In the PEITHO study, the largest trial to date involving only patients with intermediate-risk PE (n = 1,006), patients receiving the thrombolytic agent tenecteplase were significantly (p = 0.02) less likely than those receiving unfractionated heparin to develop the primary outcome, a composite of death from any cause and hemodynamic decompensation or collapse within 7 days. However, a meta-analysis of data from clinical trials of systemic thrombolytic therapy in intermediate-risk PE generally showed a lack of benefit in terms of all-cause mortality and long-term complications. Novel strategies for treatment of intermediate-risk PE, including low-dose thrombolysis and catheter-directed thrombolysis, are being investigated in an attempt to identify strategies that provide therapeutic outcomes equivalent to those provided by traditional thrombolytic modalities but with a decreased risk of bleeding. The use of thrombolysis in the treatment of intermediate-risk PE is complicated by high rates of bleeding and should be limited to patients who clinically deteriorate rather than given as a standard-of-care treatment in this population. Data for low-dose thrombolysis remain limited.

Eberle H ，Lyn R ，Knight T ，Hodge E ，Daley M ... -  《-》