Ignite Creation Date:
2024-06-16 @ 11:52 AM
Last Modification Date:
2024-10-26 @ 3:31 PM
Study NCT ID:
NCT06453876
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-06-12
First Post:
2023-12-04
Brief Title:
Percutaneous Embolectomy Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism
Sponsor:
Jesper Kjaergaard
Organization:
Rigshospitalet Denmark
Study Overview
Official Title:
Percutaneous Embolectomy Ultrasund Assisted Low Dose Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
STRATIFY-II
Brief Summary:
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
1 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
2 Thrombus burden reduction after 48-96 h is increased with percutaneous embolectomy compared to USAT with low-dose alteplase 2nd co-primary outcome
Thus the two main hypothesis being tested are
1 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
2 Thrombus burden reduction after 48-96 h is increased with percutaneous embolectomy compared to USAT with low-dose alteplase 2nd co-primary outcome
Detailed Description:
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 NCT0511161310 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
1 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
2 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
RVLV 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
1 Age 18 years
2 Informed consent for trial participation
3 Intermediate high-risk PE according to ESC criteria
4 Thrombus visible in main lobar or segmental pulmonary arteries on CT angiography
5 14 days of symptoms or less EXCLUSION CRITERIA
-- --
1 Altered mental state GCS 14
2 No qualifying CT angiography performed 24 hour since CT angiography
3 Females of child bearing potential unless negative HCG test is present
4 Thrombolysis for PE within 14 days of randomization
5 Thrombus passing through patent Foramen Ovale risk of paradoxical embolism
6 Ongoing oral anticoagulation therapy heparins aspirin antiplatelet therapy and NOAC allowed
7 Comorbidity making 6 months survival unlikely
8 Absolute contraindications for thrombolysis
1 Hemorrhagic stroke or stroke of unknown origin at any time
2 Ischemic stroke in the preceding 6 months
3 Central nervous system damage or neoplasms
4 Recent major traumasurgeryhead injury in the preceding 3 weeks
5 Gastrointestinal bleeding within the last month
6 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 flow11 12 comparing percutaneous treated groups embolectomy and USAT combined to heparinLMWH group p001 n140 vs n70
Reduction in modified Miller score score of thrombus involvement and segmental flow11 12 comparing percutaneous embolectomy and USAT p004 n70 vs n70 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 UFHLMWH 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
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 NCT0511161310 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
1 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
2 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
RVLV 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
1 Age 18 years
2 Informed consent for trial participation
3 Intermediate high-risk PE according to ESC criteria
4 Thrombus visible in main lobar or segmental pulmonary arteries on CT angiography
5 14 days of symptoms or less EXCLUSION CRITERIA
-- --
1 Altered mental state GCS 14
2 No qualifying CT angiography performed 24 hour since CT angiography
3 Females of child bearing potential unless negative HCG test is present
4 Thrombolysis for PE within 14 days of randomization
5 Thrombus passing through patent Foramen Ovale risk of paradoxical embolism
6 Ongoing oral anticoagulation therapy heparins aspirin antiplatelet therapy and NOAC allowed
7 Comorbidity making 6 months survival unlikely
8 Absolute contraindications for thrombolysis
1 Hemorrhagic stroke or stroke of unknown origin at any time
2 Ischemic stroke in the preceding 6 months
3 Central nervous system damage or neoplasms
4 Recent major traumasurgeryhead injury in the preceding 3 weeks
5 Gastrointestinal bleeding within the last month
6 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 flow11 12 comparing percutaneous treated groups embolectomy and USAT combined to heparinLMWH group p001 n140 vs n70
Reduction in modified Miller score score of thrombus involvement and segmental flow11 12 comparing percutaneous embolectomy and USAT p004 n70 vs n70 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 UFHLMWH 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None