BACKGROUND Intermediate high-risk PE is associated with an up to 10% risk of death even
if the circulations of the patient is only marginally impacted (1). Full dose
thrombolysis has been investigated is two randomized trials but finding the intervention
to be efficacious in preventing hemodynamic deterioration, but at the cost of an
increased risk og bleeding with cancels the benefit of thrombolysis with regards to risk
of death (2, 3). Therefore recent guidelines suggest that patients are managed by
heparins with thrombolysis available as a rescue therapy if the patient deteriorates
hemodynamically (1). Further two small clinical have trials have investigated the role of
low dose thrombolysis finding a substantial reduction in late incidence of pulmonary
hypertension (4) and similar efficacy of half dose thrombolysis and lower occurrence of
bleeding compared to full doses thrombolysis (5).
Since then catheter based interventions for administering low Thrombolysis for acute PE
has been introduced. Some interventionalists use simple catheters while the EKOS® system
of USAT claims to increase the efficacy of thrombolytics by applying a mechanical force
from ultrasound emitting crystals nead the emboli while slowly administering the
thrombolytics near the thrombus in the pulmonary arteries. The USAT techniques has been
tested in a small randomized trial, finding the treatment to efficacious in terms of
reducing right heart dilatation (6). Later a dose finding RCT should similar efficacy of
dosages of alteplase in USAT ranging from 4 mg to 24 mg per catheter (7). The HI-PEITHO
trial (NCT04790370) is a 406 patient trial current enrolling patients, and the STRATIFY
trial from our group (NCT04088292) is a 210 patient trial also currently including
patients, and thus more knowledge of the efficacy of this approach will be available in
1-2 years.
Recently catheter-based embolectomy has been introduced. While no randomized trials have
compared this technique to the guidelines supported strategy of UFH or LMWH, several
registries and sace series have been put forward, suggesting a significant efficacy and a
acceptable risk of bleeding. The INARI FlowTriever system ® has been use in a substantial
number of patients, but have only been reported in none peer-reviewed presentation as
results of two registries comparing patients treated with percutaneous embolectomy and a
registry describing 'real world data' has been presented online (8) and in comment
section in medical journals (9). An ongoing randomized trial comparing percutaneous
embolectomy and catheter directed thrombolysis, is currently recruiting patients
(NCT05111613)(10) and another comparing embolectomy and heparins is planned
(NCT06055920).
Balancing the risk and efficacy of the treatment strategy remains important and since a
lack of data both proving the efficacy of the novel treatment alternatives and limited
data comparing efficacy in trial with a suitable design, a clinical equipoise remains.
TRIAL OBJECTIVES AND HYPOTHESIS The STRATIFY II trial investigates the efficacy of three
different approaches to reducing thrombus burdon in patients with acute intermediate
high-risk pulmonary embolism: percutaneous embolectomy (the Flow Triever® system, INARI
medical), USAT (EKOS® system, Boston Scientific with low dose alteplase) and heparin with
the option to perform full-dose thrombolysis. As a co-primary secondary end point the
trial assess the incremental efficacy of the embolectomy vs the catheter based low dose
thrombolysis approach.
Thus the two main hypothesis being tested are:
Thrombus burden reduction after 48-96 h is increased with a catheter based
(embolectomy or USAT) compared to the a heparin with optional high dose thrombolysis
approach (1st co-primary outcome)
Thrombus burden reduction after 48-96 h is increased with percutaneous embolectomy
compared to USAT with low-dose alteplase (2nd co-primary outcome) SETTING AND
PATIENT POPULATION SETTING The trial is including patients diagnosed with an acute
PE (defined as symptom duration of less than 14 days) with intermediate- high risk ,
please see section of definition below. Patients are recruited from participating
centers by the attending cardiologist, either in the emergency room or at the ward.
Since risk stratification most often involves a cardiologist the investigators
expect the majority of patients to be included in the trial immediately after risk
stratification.
The participants will be informed on the possible inclusion in the trial in the ward, and
every measure possible will be taken to ensure a quit environment for the information.
The patient will be informed about their right to have an assessor present during the
information session, and that they may take the time needed to consider their
participation in the trial and giving their informed consent. The informed consent will
be obtained soon after the patient have been informed on their diagnosis of
intermediate-high risk PE.
DEFINITIONS Definition of Intermedidate- high risk PE is based on ESC guideline
classification from 2019 (1) as identification of PE in the pulmonary main trunk, main
and segmental pulmonary arteries on CT angiography performed as part of the diagnostic
work-up of patients with clinical suspicion of acute PE RV dysfunction is defined as
RV/LV ratio of > 1 on CT angiography or echocardiography (apical 4 chamber view
in-diastole) OR
RV systolic function by visual assessment or TAPSE < 18 mm OR
TR gradient > 40 mmHg Elevated Cardiac Biomarker
Increase in cardiac Troponins (I or T) above normal OR
Increase Creatine Kinase MB (CKMB) above normal OR
Increase in NT-pro-BNP above normal In the absence of shock at time of screening
defined as
Systolic blood pressure > 100 mmHg INCLUSION CRITERIA
Age ≥ 18 years
Informed consent for trial participation
Intermediate high-risk PE according to ESC criteria
Thrombus visible in main, lobar or segmental pulmonary arteries on CT
angiography
14 days of symptoms or less EXCLUSION CRITERIA
Altered mental state (GCS < 14)
No qualifying CT angiography performed (> 24 hour since CT angiography)
Females of child bearing potential, unless negative HCG test is present
Thrombolysis for PE within 14 days of randomization
Thrombus passing through patent Foramen Ovale (risk of paradoxical embolism)
Ongoing oral anticoagulation therapy (heparins, aspirin, antiplatelet therapy
and NOAC allowed)
Comorbidity making 6 months survival unlikely
Absolute contraindications for thrombolysis
Hemorrhagic stroke or stroke of unknown origin at any time
Ischemic stroke in the preceding 6 months
Central nervous system damage or neoplasms
Recent major trauma/surgery/head injury in the preceding 3 weeks
Gastrointestinal bleeding within the last month
Known bleeding risk Relative contraindications do not preclude
randomization. Relative contraindications include: Transient ischemic
attack in the preceding 6 months, Oral anticoagulant therapy, Pregnancy,
or within one week post partum, Non-compressible puncture site, Traumatic
resuscitation, Refractory hypertension (systolic blood pressure >180 mm
Hg), Advanced liver disease, Infective endocarditis, Active peptic ulcer
OUTCOMES CO-PRIMARY ENDPOINT
Reduction in modified Miller score (score of thrombus involvement and segmental
flow)(11, 12) comparing percutaneous treated groups (embolectomy and USAT combined)
to heparin/LMWH group, p<0.01 (n=140 vs. n=70).
Reduction in modified Miller score (score of thrombus involvement and segmental
flow)(11, 12) comparing percutaneous embolectomy and USAT, p<0.04 (n=70 vs n=70)
SECONDARY ENDPOINTS
• Bleeding complications (major and minor bleeding complication according to the
Thrombolysis in Myocardial Infarction classification)
Duration of index admission, including hospital-based rehabilitation
Dyspnoea index (Visual analogue scale) after 48-96 h and after 3 months
FiO2, blood pressure, and respiratory rate, heart rate at time of follow-up CTPA
Mortality in the three groups (log-rank), and hazard ratio in multivariable analysis
using the UFH/LMWH as a reference
Incidence of TR gradient > 40 mmHg at 3 months follow-up echocardiography
6MWT at 3 months follow up comparing the three groups
Quality of life at 3 months follow-up comparing the three groups (PEmb-Qol and
5Q-5D-5L)