PERSEVERE (ClinicalTrials.gov Identifier: NCT06588634) is a multinational randomized controlled open-label superiority trial comparing LBMT with the FlowTriever system versus SoC in High-Risk PE. The primary objective is to assess whether LBMT plus anticoagulation is associated with a significant reduction in the composite outcome of all-cause death, cardiac arrest, bailout to an alternative therapeutic strategy or major bleeding occurring until hospital discharge or day 7 post randomization (whichever comes first), or ECMO in place on day 7 after randomization, as compared to SoC. Allocation to treatment arm is known to investigators and patients, but adjudication of the primary outcome and safety outcomes will be performed by a Clinical Events Committee (CEC). In addition, safety events are monitored by an independent Data Safety Monitoring Board.

All adult patients presenting to hospital for evaluation and treatment of PE will be evaluated for potential inclusion in the trial. In patients with symptom onset ≤2 weeks, clinical assessment, along with standard-of-care imaging (eg, computed-tomography [CT] pulmonary angiography and/or echocardiography), will be conducted to diagnose acute PE with hemodynamic instability and RV dysfunction (defined as RV/left ventricle [LV] ratio ≥1.0) prior to randomization. Inclusion and exclusion criteria are listed in Table 1 . Key inclusion criteria, capturing both hemodynamic and respiratory forms of High-Risk PE, are a proximal pulmonary filling defect along with 1 or more of the following: (1) systolic hypotension or need for vasopressors; (2) venous lactate ≥4 mmol/L and clinical signs suggesting obstructive shock; (3) need for extracorporeal membrane oxygenation (ECMO) support prior to randomization (eg, for acute refractory cardiovascular failure, rapidly progressing cardiogenic shock, or following short-duration cardiopulmonary resuscitation); or (4) a resuscitated cardiac arrest. These criteria largely correspond to the definition of High-Risk PE in current guidelines. On the other hand, we also opted for a higher serum lactate threshold of 4 mmol/L compared to 2.5 mmol/L in current guidelines to better identify a higher risk cohort most likely to benefit from pulmonary reperfusion therapy. This approach was based on evidence from the FLASH registry showing that lower lactate levels (around 2.5 mmol/L) were common in intermediate-risk PE without increased mortality, while lactate levels around 4 mmol/L have been identified as mortality predictors in cardiogenic shock, both in RCTs (mean 4.7 ± 2.3 mmol/L) and registries (mean 5.9 ± 1.9 mmol/L) . ^,, Notably, a substantial proportion of patients with clinical signs of obstructive shock and elevated lactate may be normotensive; with these criteria, approximately 5-10% of all PE cases could be considered High-Risk. ^, Exclusion criteria include prolonged cardiac arrest (with associated persistence of loss of consciousness or neurological deficiency), CT evidence of chronic thromboembolic pulmonary hypertension, or an absolute contraindication to ST (ie, cranial or spinal surgery or stroke in the past 14 days, intracranial tumor, or life-threatening active bleeding).

Patients will be randomized after providing written informed consent, or, if the patient is unable, consent may be obtained via a legally authorized representative. As a third option, emergency (deferred) consent may be obtained (at European sites only), provided it is compliant with IRB/EC approvals and adheres to regulatory, ethical and national standards.

The flowchart of the study is shown in Figure 1 . The Initial Treatment Plan (Primary Index Therapy) is a predefined therapy or set of therapies determined at the initiation of patient care to address the primary condition and according to the randomized treatment allocation. Assignment to either treatment arm (LBMT or SoC) requires initiation of therapeutic anticoagulation as soon as possible following diagnosis. In both arms, anticoagulation will be administered using low-molecular-weight heparin (LMWH) or any other regimen approved for acute PE treatment, according to local practice and at the discretion of the investigator. It is recommended that transition to oral anticoagulation occur no earlier than 48 hours after initiation of the randomized intervention, but the decision is based on the investigator’s clinical judgment. In addition, ECMO may be used in both arms as part of a combinatory strategy for primary treatment.

Overview of the PERSEVERE trial design ( ClinicalTrials.gov Identifier: NCT06588634).

^a The Standard of Care arm may include systemic thrombolysis, surgical embolectomy, anticoagulant therapy alone, or ECMO as a stand-alone therapy. Catheter-directed thrombolysis is not permitted within the SOC arm and should only be considered as bailout therapy, triggering the primary endpoint of the trial. AE, adverse event; ECMO, extra-corporeal membrane oxygenation; LBMT, large-bore mechanical thrombectomy; PE, pulmonary embolism; SoC, standard of care.

Patients allocated to the LBMT arm will be managed with the FlowTriever Retrieval/Aspiration System. The FlowTriever system is an over-the-wire catheter-based device designed for the percutaneous treatment of pulmonary arterial thromboembolism. The system consists of 2 main components, which are packaged separately: Triever catheters for aspiration (available in 3 sizes: 16, 20, and 24 Fr) and the FlowTriever catheters for mechanical disruption and retrieval, which consist of 3 self-expanding nitinol mesh disks (available in 4 sizes: 6-10 mm, 11-14 mm, 15-18 mm, and 19-25 mm) or a nitinol basket (available in 1 size: 6-16 mm). First, venous puncture is achieved under ultrasound guidance. Angiography of the pulmonary arterial system is recommended (but at the operator’s discretion, depending on the patient’s clinical status), as is assessment of pulmonary artery pressure and cardiac output, enabling direct comparison of these parameters before and after thrombectomy. The Triever catheter is then inserted and advanced over an 0.035” guidewire placed in a pulmonary arterial branch to reach the thrombus. The procedure is conducted under fluoroscopic/angiographic guidance. Once the dilator is removed, the thrombus can be aspirated using the included 60-cc vacuum syringe, and aspirated blood can be filtered of thrombus and returned to the patient using the FlowSaver autologous blood return system. FlowTriever catheters can optionally be used to mechanically engage and retrieve the thrombus before aspiration. Intraprocedural anticoagulation is as per local standard of care (using the partial thromboplastin time or activated clotting time). Upon completing the procedure, the catheter is removed from the patient, and vascular closure is achieved according to local practice.

Participants in the SoC arm will receive therapy per local practice standards with encouragement to adhere to evidence-based guidelines for the management of acute PE. ^, ST (administered as full-dose or accelerated reduced-dose therapy) is encouraged for patients in whom the benefits of thrombolysis outweigh the risk of bleeding, based on the clinical team’s judgment. Surgical embolectomy, stand-alone ECMO therapy, or anticoagulation alone are also acceptable as primary therapy options in the SoC arm per the clinical team’s discretion. CDT is not permitted as a primary therapeutic approach in the SoC arm, although it can be considered as a bailout option if necessary, an intervention which would trigger the primary endpoint of the study.

In both groups, the assigned Primary Index Therapy must be initiated no later than 4 hours postrandomization. If the Primary Index Therapy includes ECMO in addition to advanced therapy, eg, in the case of planned ECMO to support delivery of the allocated therapy as part of the initial therapeutic strategy, then ECMO should be started as early as possible, and no later than 6 hours after randomization. Sites are encouraged to administer treatment as expeditiously as possible to optimize patient outcomes.

An overview of the tests to be performed and parameters to be collected upon enrollment and at the follow-up visits is provided in Table 2 . The primary and secondary endpoints of the trial are presented in Table 3 . The primary endpoint is a composite of events occurring through the earlier of hospital discharge or 7 days after randomization, encompassing all-cause death, cardiac arrest requiring cardiopulmonary resuscitation, bailout to an alternative therapeutic strategy following criteria clearly defined in the protocol, major bleeding, and ECMO life support in place on day 7 postrandomization. Major bleeding is defined according to the Bleeding Academic Research Consortium (BARC) definition, including types 3b, 3c, 5a, and 5b. Bailout therapy will be adjudicated by the CEC and is defined as an unplanned escalation of therapeutic measures after initiation of Primary Index Therapy, when the patient’s condition has not improved or is not improving in line with expectations during the index hospitalization or is deteriorating. Bailout therapy can include 1 or more of the following: change from the assigned treatment strategy, unplanned use of additional therapy, initiation of unplanned ECMO after the Primary Index Therapy has started, or late initiation of planned ECMO. Any 1 or more of the following conditions of acute refractory cardiovascular failure qualifies a patient for bailout therapy: cardiac arrest after randomization, requiring cardiopulmonary resuscitation; persistent or rising venous lactate elevation of ≥2 mmol/L, despite adequate intravascular volume status, and clinical signs suggesting hypoperfusion (eg, acute alteration in mental status, cold and clammy skin, extensive skin mottling); sustained hypotension with persistently high or escalating doses or increasing numbers of vasoactive drugs to maintain or improve perfusion; or requirement to markedly increase supplemental oxygen, or need for mechanical ventilation to treat ongoing respiratory distress with refractory hypoxemia. For instance, a patient who develops cardiac arrest following thrombectomy and requires initiation of ECMO support more than 6 hours after randomization, or one who fails to improve after systemic thrombolysis and subsequently undergoes surgical embolectomy, would both meet the criteria for bailout therapy. We elected to apply a lower lactate threshold for bailout than for inclusion. Indeed, the association between lactate levels ≥2 mmol/L and increased mortality is well documented, and it would not be ethically acceptable to leave patients in a state of persistent hypoperfusion following reperfusion therapy (in either group) if any degree of hypoperfusion remains.

Table 2

Trial visit plan and data collection schedule

Assessment	Baseline (≤48h prior to randomization)	Primary index therapy/index procedure (≤4h postrandomization) ║,¶	72-h visit (± 24 h) ††	Hospital discharge	3-mo visit (90-120 d)	Unscheduled visit
Informed consent	X
Inclusion/exclusion review †	X
Demographics and medical history	X
Acute PE confirmation †	X
Anticoagulation regimen	X	X	X	X	X	X
Clinical labs ‡	X		X ‡‡	X ║║	X ‡‡	X ‡‡
Cardiac imaging	CTPA and/or echo		Echo	Echo ║║	Echo	Echo ¶¶
Randomization		X (Time 0 for visit calculation)
Primary index therapy data		X
Dyspnea assessment (Modified medical research council (mMRC) and Modified borg dyspnoea scale (MBS))	X		X	X	X
Oxygenation status	X	X	X	X	X
NYHA/WHO functional assessment	X		X		X
QoL assessments (PEmb-QoL, EQ-5D-5L, PVFS)					X
6-minute walk test			X ‡‡		X ‡‡
PPEI assessment (derived)			X §§	X §§	X	X ‡‡
Return to work/prior status					X
Discharge status				X
Adverse event assessment §	X	X	X	X	X	X
ICU stays	X	X	X	X	X	X

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