Percutaneous Embolectomy, Low Dose Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism (STRATIFY II)

Percutaneous Embolectomy, Low Dose Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism (STRATIFY II)

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 AlphaVAC(R), AngioDynamics or the Flow Triever® system, INARI medical), Low intravenous thrombolysis (Alteplase 10 mg) 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 low-dose alteplase) 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 low-dose alteplase (2nd co-primary outcome)

Background: Intermediate-high risk pulmonary embolism (PE) is associated with a significant risk of death or hemodynamic deterioration. The optimal treatment strategy should balance efficacy in reducing thrombus burden and hemodynamic compromise with risk of complications, in particular bleeding. Previous studies have investigated conventional high-dose, short term thrombolysis by recombinant tissue Plasminogen Activator (rtPA), finding a reduction in risk hemodynamic deterioration, but not in mortality, and a substantial increase in significant bleeding complications.

Percutaneous catheter-based techniques of embolectomy or low dose thrombolysis may offer lower risk of complication while still being efficacious. A clinical equipoise remains as data from RCTs of reasonable size remain to be published.

The current trial addresses this paucity of data by randomizing patients to one of three treatment modalities:

Design: Regional collaborative, randomized trial with 1:1:1 allocation of 210 patients with acute intermediate-high risk PE and no absolute contraindications to thrombolysis Intervention: 1:1:1 randomization (stratified for index hospital) to

• Percutaneous Embolectomy plus unfractionated heparin (UFH) or low molecular weight heparin (LMWH) within 12 hours of randomization.

• Low dose thrombolysis (10mg of rtPA, Alteplase) over 6 hours plus UFH or lLMWH within 12 hours of randomization.

• UFH or LMWH only (with option for conventional thrombolysis according to local protocols for hemodynamic deterioration) Inclusion criteria: 1) Age ≥ 18 years, 2) Intermediate high-risk PE according to ESC criteria AND 3) Class II risk assessed by the Pulmonary Embolism Severity Index (1). 4) Thrombus visible in main, lobar or segmental pulmonary arteries on CT angiography 5) 14 days of symptoms or less, with significant worsening of symptoms within 7 days Exclusion criteria: 1) Glasgow Coma Scale Score < 14, 2) qualifying CT angiography> 24 hours prior to screening, 3) pregnancy, 4) Thrombolysis for PE within 14 days of randomization 5) Thrombus passing through patent Foramen Ovale, 6) Ongoing oral anticoagulation therapy (heparins, aspirin, antiplatelet therapy and NOAC allowed), 7) Comorbidity making 6 months survival unlikely. 8) Absolute contraindications for thrombolysis(2) Primary outcome: 2 Co-primary outcomes: Reduction in refined modified Miller Score (rmMS) on follow-up (48-96 h) CT pulmonary Angiography comparing catheter-based interventions to UFH/LMWH group (p<0.01, N=210) and reduction in refined Miller Score on follow-up (48-96 h) CT pulmonary Angiography comparing percutaneous embolectomy to low-dose rtPA, p<0.04, N=140). Secondary outcomes: 1) Bleeding complications (major and minor bleeding complication according the FRISC classification) 2) Duration of index admission, including hospital based rehabilitation. 3) Dyspnoea index (Visual analogue scale) after 48-96 h and after 3 months, 4) FiO2, Blood pressure, and respiratory rate, heart rate at time of follow-up CT angiography, 5) Mortality in the three groups (log-rank), and hazard ratios in multivariable analysis using the UFH/LMWH group as reference. 6) Incidence of TR gradient > 40 mmHg at 3 months follow-up echocardiography. 10) 6MWD at 3 months comparing the three groups. 11) Quality of life at 3 months follow-up comparing the three groups (EQ-5Q-5L) Predefined design variables are sex, age above median, known renal failure GFR (<30 ml/min or current renal replacement therapy), Chronic Obstructive Pulmonary Disease, 'saddle' embolus, syncope or CPR performed.

INCLUSION CRITERIA

1. Age ≥ 18 years
2. Intermediate high-risk PE according to ESC criteria
3. Class II risk assessed by the Pulmonary Embolism Severity Index (1).
4. Thrombus visible in main, lobar or segmental pulmonary arteries on CT angiography
5. 14 days of symptoms or less, with significant worsening of symptoms within 7 days

EXCLUSION CRITERIA

1. Altered mental state (GCS < 14)

2. No qualifying CT angiography performed (> 24 hour since CT angiography)

3. Women of childbearing 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. History of haemorrhagic stroke or stroke of unknown origin
   2. Ischaemic stroke in previous 6 months
   3. Central nervous system neoplasm
   4. Major trauma, surgery, or head injury in previous 3 weeks
   5. Bleeding diathesis - Active bleeding