Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism (STRATIFY)

Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism

Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism

Herlev and Gentofte Hospital, University Hospital Bispebjerg and Frederiksberg, Hillerod Hospital, Denmark, Copenhagen University Hospital, Hvidovre

Open label clinical randomized trial comparing three strategies for managing acute intermediate-high risk pulmonary embolism

Trial acronym: STRATIFY 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 (rtPA), finding a reduction in risk hemodynamic deterioration, but no reduction in mortality and a substantial increase in significant bleeding complications. Catheter based techniques and low dose thrombolysis may offer lower risk of complication with reasonable efficacy. Such studies have not been performed in RCTs with a reasonable sample size, and no study have compared low dose intravenous thrombolysis and catheter based techniques. The current trial addresses this paucity of data by randomizing patients to one of three treatment modalities: Intervention: 1:1:1 randomization, stratified for site to UltraSound Assisted Thrombolysis (USAT) with low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus unfractionated heparin (UFH) or low molecular weight heparin (LMWH) within 12 hours of randomization Intravenous low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus UFH or low molecular weight heparin (LMWH). UFH or low molecular weight heparin (LMWH) only (with option for conventional thrombolysis according to local protocols for hemodynamic deterioration) Design: Regional collaborative, randomized trial with 1:1:1 allocation of 210 patients with acute intermediate-high risk PE with no absolute contraindications to thrombolysis

UltraSound Assisted Thrombolysis (USAT) with low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus unfractionated heparin (UFH) or low molecular weight heparin (LMWH) within 12 hours of randomization

Intravenous low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus UFH or low molecular weight heparin (LMWH).

UFH or low molecular weight heparin (LMWH) only (with option for conventional thrombolysis according to local protocols for hemodynamic deterioration)

Reduction in Miller Score and on follow-up (48-96 h) CT pulmonary Angiography comparing low-dose rtPA (±USAT) to UFH/LMWH group (p<0.01, N=210)

reduction in Miller Score and on follow-up (48-96 h) CT pulmonary Angiography comparing low-dose rtPA by USAT to iv, p<0.04, N=140)

Mortality in the three groups (log-rank), and hazard ratio in multivariable analysis using the UFH/LMWH as reference

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