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

Summary: 
      Acute pulmonary embolism (PE) accounts for 5-10% of in-hospital deaths. Systemic
      anticoagulation (AC) is the standard of care and thrombolysis is recommended for those at a
      higher mortality risk. Catheter-directed therapies, mainly standard infusion catheter
      thrombolysis (CDT) and ultrasound-accelerated thrombolysis (USAT), have been introduced as
      new more effective and safer treatment modalities. USAT is a modification of standard
      catheter lysis utilizing a system of local ultrasound to dissociate the fibrin matrix of the
      thrombus with simultaneous acoustic streaming of the thrombolytic agent, allowing more
      efficient thrombolysis. However, there is limited comparative effectiveness data against
      standard multi-side hole catheter infusion. More rapid clearance of pulmonary thrombus by
      USAT compared to standard CDT may prove to be clinically beneficial and cost effective.
      Alternatively, if thrombus clearance is similar, the cost of USAT may exceed the cost of CDT
      (equipment and disposables), without realization any advantage.
    

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. 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. CTEPH 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%).11 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
      with simultaneous acoustic streaming of the infusate, 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. 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. The University of
      Pittsburgh group's 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. 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): catheter-directed thrombolysis
Intervention type(s): Procedure
Intervention description(s): catheter-directed thrombolysis with commercially available multi-sidehole catheter or USAT catheter
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment