Standard vs. Ultrasound-assisted Catheter Thrombolysis for Submassive Pulmonary Embolism
Condition: Pulmonary Embolism
MeSH terms: Pulmonary Embolism; Embolism
Study type: Interventional

Summary: 
      The study will compare standard catheter directed thrombolysis to ultrasound accelerated
      thrombolysis for the treatment of acute submassive pulmonary embolism (PE). The study
      population will include patients eligible for catheter directed thrombolysis (CDT) for
      submassive PE. Subjects will be randomized to, either, standard catheter-directed
      thrombolysis or ultrasound-accelerated thrombolysis (USAT).
    

Detailed description: 
      Acute pulmonary embolism (PE) carries a high morbidity and is the third-leading cause of
      cardiovascular mortality in the western world. It accounts for 5-10% of in-hospital deaths
      that for the United States translates to 200,000 deaths per year.1 Recent registries and
      cohort studies suggest that approximately 10% of all patients with acute PE die during the
      first 1 to 3 months after diagnosis. Studies that have observed survivors for >3 months have
      reported an incidence of chronic thromboembolic pulmonary hypertension (CTEPH) 1-5% within
      2-3 years after PE.6-10 It is an incapacitating long-term complication of thromboembolic
      disease with a negative impact on the patient's quality of life and prognosis.

      The management acute PE is mainly guided by the acuity and severity of clinical presentation.
      Initial systemic anticoagulation (AC) is the standard of care and treatment is escalated
      based on the clinical presentation and patient characteristics that may stratify them at a
      higher mortality risk. The goals of therapy are to primarily prevent mortality, and
      secondarily potentially prevent late onset chronic thromboembolic pulmonary hypertension
      (CTEPH) and improve quality of life.

      Massive PE is defined as PE associated with sustained hemodynamic instability, whereas
      submassive PE (sPE) is defined as PE without hemodynamic instability but with abnormal right
      ventricular (RV) function and/or evidence of myocardial necrosis. It is notable that there is
      ongoing interest to accurately risk stratify sPE to identify the patients who are at
      increased risk of decompensating and/or dying. Clinical scores, imaging tests and biomarkers
      are under investigation, yet an ideal prognostic tool is still pending. A novel cardiac
      biomarker, heart-type fatty acid-binding protein (h-FABP), is emerging as a significant
      predictor of mortality in patients with submassive PE.

      Systemic intravenous thrombolysis is universally recommended by all guideline bodies for
      massive pulmonary embolism, but remains controversial for submassive PE. In the most recent
      metaanalysis, the subgroup analysis of 8 submassive PE trials (1993-2014, n=1775) showed that
      thrombolytic therapy was associated with a mortality reduction (1.39% vs 2.92%) but with an
      increase in major bleeding (7.74% vs 2.25%). These results were mainly driven by the largest
      randomized trial (PEITHO, 1006 patients) which compared a single, weight-adapted i.v. bolus
      of tenecteplase with standard anticoagulation.

      The recent development of catheter-directed therapies such as catheter-directed thrombolysis
      (CDT), ultrasound-accelerated thrombolysis (USAT), and pharmacomechanical or aspiration
      thrombectomy has introduced more tools for the treatment of acute PE. Proponents of these
      techniques suggest that they may provide a similar therapeutic benefit as systemic
      thrombolysis, while decreasing the dose of thrombolytic required and potentially decreasing
      the risk of adverse bleeding events. Both the American Heart Association and more recently
      European Society of Cardiology have acknowledged CDT as a viable treatment alternative for
      high risk acute sPE (echocardiographic RV dysfunction and elevated cardiac biomarkers), if
      appropriate expertise is available and particularly when the bleeding risk is high.

      Catheter-directed thrombolysis requires placement of a multi-sidehole infusion catheter
      within the pulmonary arterial thrombus burden under angiographic guidance. Thrombolytic
      medications are slowly infused through the catheter, which is left in place for the duration
      of the treatment. USAT is a modification of this therapy utilizing a proprietary system of
      local high frequency, low-power ultrasound to dissociate the fibrin matrix of the thrombus,
      allowing deeper penetration of lytic medication.

      Several observational non-controlled series have demonstrated the efficacy of
      catheter-directed techniques in improving clinical and hemodynamic parameters and reducing
      clot burden while demonstrating a favorable safety profile. The ULTIMA trial was the first
      randomized controlled trial to include CDIs for sPE comparing standardized fixed-dose of USAT
      (10mg rtPA per lung over 15 hours) and AC to AC alone. In the USAT group, but not in the
      heparin group, the mean RV/LV ratio was significantly reduced at 24 hours, but became
      comparable between the two groups at 90 days. The RV systolic function was significantly
      improved in the USAT group vs. the heparin group at both 24 hours and 90 days. In both study
      groups minor bleeding complications were rare and there were no major bleeding complications.
      The SEATTLE II trial, a single-arm study evaluating the effectiveness of USAT, showed also an
      RV/LV ratio improvement at 48 hours.

      Limited data exists for comparing different catheter-directed therapies for acute PE. The
      majority of recent series for catheter-directed interventions utilize USAT exclusively;
      however there is limited comparative effectiveness data comparing this modality to standard
      multi-sidehole catheter infusion. Preliminary, non-controlled data are conflicting. One
      series by Lin and colleagues of 33 high-risk PE patients suggested benefit for USAT for
      angiographic clearance of thrombus burden with more bleeding events in the CDT group.31 Kuo
      and colleagues noted no difference in outcomes and treatment specifics between USAT and CDT
      in the recently published early results of a multicenter prospective registry. Our
      retrospective analysis of 63 patients suggests that there may be no difference between the
      two treatment modalities, demonstrating similar rates of outcomes such as survival,
      hemodynamic stabilization, and echocardiographic parameters in both groups with similar
      procedure length and lytic dose in the time-adjusted cohorts. Selection bias cannot be
      underestimated in all these studies.

      The expected benefit of USAT has been dependent on the device's ability to increase
      penetration of lytic into thrombus using high frequency, low power ultrasound, due to its
      reversible effects on fibrin dissociation. This benefit has been shown to result in faster
      thrombus clearance in selected vascular beds in some studies, such as the recently published
      DUET study comparing USAT and CDT in arterial occlusions. More rapid clearance of pulmonary
      thrombus by USAT compared to standard CDT may prove to be clinically and cost effective (e.g.
      via reduced length of ICU and hospital stay). Alternatively, if thrombus clearance is
      similar, the cost of USAT may exceed the cost of CDT (proprietary equipment and disposables),
      without offering any potential advantage. Evidence from the venous circulation, coming from
      the recent BERNUTIFUL trial demonstrated no difference in time to thrombus clearance in lower
      extremity deep venous thrombosis.
    

Intervention name(s): CDT without ultrasound acceleration; CDT with ultrasound acceleration
Intervention type(s): Procedure; Procedure
Intervention description(s): A pulmonary arteriogram will be performed. Upon confirmation of the pulmonary embolus a standard infusion catheter will be placed within the clot. The catheter will be used for infusion of thrombolytics to treat/dissolve the pulmonary embolus.; A pulmonary arteriogram will be performed. Upon confirmation of the pulmonary embolus an infusion catheter that incorporates an ultrasound emitting wire will be placed within the clot. The catheter will be used for infusion of thrombolytics to treat/dissolve the pulmonary embolus. The wire will be connected to an ultrasound generating device.
Other intervention name(s): Standard CDT; Ultrasound assisted CDT
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: acute pulmonary embolism; submassive pulmonary embolism; thrombolysis; catheter directed thrombolysis; ultrasound assisted thrombolysis