Surgical Pulmonary Embolectomy Versus Catheter-directed Thrombolysis in the Treatment of Pulmonary Embolism: A Non-inferiority Study
Condition: Acute Pulmonary Embolism (PE)
MeSH terms: Pulmonary Embolism; Embolism
Study type: Interventional

Summary: 
      Acute pulmonary embolism (PE) is a serious and potentially lethal condition. The clinical
      spectrum of PE spans from asymptomatic PE to patients with severe hemodynamic compromise. The
      main determinant of outcome is right ventricular dysfunction caused by the abrupt rise in
      pulmonary vascular resistance. Patients with hemodynamic compromise are at highest risk of
      mortality (>15%). Hemodynamic stable patients with imaging and biomarker evidence of right
      ventricular (RV)- dysfunction are at intermediate-high risk of mortality (3-15%). According
      to the European Society of Cardiology (ESC) guidelines reperfusion therapy options for
      patients at high risk and at intermediate-high risk include systemic thrombolysis,
      catheter-directed therapy or surgical embolectomy.

      The University Hospital of Bern is the only tertiary care hospital in Switzerland that has
      established an interdisciplinary pulmonary embolism response team (PERT since 2010) and has
      gained expertise in both catheter-directed thrombolysis and surgical embolectomy. Since the
      introduction of PERT, systemic thrombolysis was no longer performed in Bern due to the high
      risk of intracranial hemorrhage. Favorable clinical outcomes of the patients managed in Bern
      have been published for both catheter-directed therapy and surgical embolectomy.

      To date, no study has ever compared catheter-directed thrombolysis versus surgical pulmonary
      embolectomy in the treatment of high and intermediate-high risk PE patients.
    

Detailed description: 
      Background and Study Rationale:

      Acute pulmonary embolism (PE) is a serious and potentially lethal condition. The clinical
      spectrum of PE spans from asymptomatic PE to patients with severe hemodynamic compromise. The
      main determinant of outcome is right ventricular dysfunction caused by the abrupt rise in
      pulmonary vascular resistance. Patients with hemodynamic compromise are at highest risk of
      mortality (>15%). Hemodynamic stable patients with imaging and biomarker evidence of right
      ventricular (RV)- dysfunction are at intermediate-high risk of mortality (3-15%). According
      to the European Society of Cardiology (ESC) guidelines reperfusion therapy options for
      patients at high risk and at intermediate-high risk include systemic thrombolysis,
      catheter-directed therapy or surgical embolectomy.

      The University Hospital of Bern is the only tertiary care hospital in Switzerland that has
      established an interdisciplinary pulmonary embolism response team (PERT since 2010) and has
      gained expertise in both catheter-directed thrombolysis and surgical embolectomy. Since the
      introduction of PERT, systemic thrombolysis was no longer performed in Bern due to the high
      risk of intracranial hemorrhage. Favorable clinical outcomes of the patients managed in Bern
      have been published for both catheter-directed therapy and surgical embolectomy.

      To date, no study has ever compared catheter-directed thrombolysis versus surgical pulmonary
      embolectomy in the treatment of high and intermediate-high risk PE patients.

      Primary Objective:

      Non-inferiority of catheter-directed thrombolysis to surgical pulmonary embolectomy regarding
      efficacy in reversal of RV dilatation in high and intermediate -high risk patients with acute
      pulmonary embolism.

      Number of Patients:

      60 patients (30 with surgical pulmonary embolectomy and 30 with catheter-directed
      thrombolysis therapy) Number of Centers: 1

      Study Patient Treatment:

      All patients will receive standard anticoagulant therapy. In a 1:1 fashion, patients will be
      randomized to undergo catheter-directed thrombolysis or surgical pulmonary embolectomy.
      Stratification will be performed by the presence of high-risk pulmonary embolism.

      Trial Duration: 24 months Start Date: October 2015 Stop Date: June 2017 Publication: 2017
      Standard Therapy Anticoagulation is the main therapy for acute PE once the diagnosis is
      established. The main objectives of anticoagulant therapy in the initial treatment are to
      prevent thrombus extension and secondary recurrence of venous thromboembolism. Current
      guidelines recommend an initial treatment for at least 5 days with either subcutaneous
      low-molecular-weight heparin (LMWH), intravenous or subcutaneous unfractioned heparin, or
      subcutaneous fondaparinux as well as the initiation of oral vitamin-K antagonists at the same
      time. 6 In addition to anticoagulation, the recent European Society of Cardiology (ESC)
      guidelines recommend systemic thrombolysis in PE patients at high risk of death (Grade 1B)
      and should be considered in patients at intermediate-high risk of death.6 However, recent
      evidence shows that hemodynamic decompensation is prevented in patients with
      intermediate-high risk PE, but the incidence of major bleeding complications (20%) and
      intracranial hemorrhage (up to 3%) increased significantly.8 Therefore systemic fibrinolytic
      therapy is withheld in the majority of cases mainly due to the fear of life-threatening
      bleeding complications including intracranial hemorrhage. 4 Due to the high risk of
      intracranial bleeding complications, systemic thrombolysis therapy is no longer performed at
      the Inselspital Bern.

      Given that high and intermediate-high risk PE patients require special attention, a
      standardized procedure is provided to these patients by an established pulmonary embolism
      response team (PERT) at the Inselspital in Bern. The pulmonary embolism response team
      consists of an angiologist, a cardiologist, an emergency physician, and a cardiac surgeon
      available 24 hours a day, and 7 days a week. Each patient is evaluated whether he/she is best
      treated by anticoagulation only or additional catheter-directed thrombolysis or surgical
      pulmonary embolectomy is indicated. Hereby, an already established standardized clinical
      algorithm is used to guide treatment procedures depending on the individual risk setting
      (Appendix 5).

      It should be emphasized, that this clinical pathway in Bern is only possible due to the fact,
      that there is an experienced interdisciplinary and standardized approach to patients with
      pulmonary embolism. Pulmonary embolism response teams (PERT) are established in several
      academic hospitals in the United States of America, including the Brigham and Women's
      Hospital and the Massachusetts General Hospital, both in Boston, Harvard Medical School. The
      University Hospital Bern has established the first interdisciplinary PERT in Europe in 2010
      and remains the only European academic hospital offering both surgical embolectomy and
      catheter therapy on a 24 basis to patients with acute pulmonary embolism at increased risk of
      death. The Cardiovascular Center of the University Hospital Bern belongs to one of the few
      hospitals worldwide that has clinical experience in both surgical embolectomy and catheter
      therapy. Excellent clinical results were published for both techniques. Therefore, the
      University Hospital Bern has the unique opportunity to perform a randomized controlled
      clinical trial and compare both techniques. A large multicenter trial powered for a mortality
      analysis would be ideal to investigate the efficacy and safety of both techniques. A clinical
      trial designed for non-inferiority would require more than 1000 patients enrolled from over
      50 centers. However, due to the fact that PERTs are not yet established in Europe, we intend
      to perform a single center study in Bern using surrogate endpoints, i.e. reversal of right
      heart failure and reduction in thrombus load. The study will not be powered for clinical
      endpoints but will assess secondary endpoints, including mortality, bleeding complications,
      exercise performance, and quality of life up to 12 months after the revascularization
      procedure.

      Revascularization Strategies The main objective of early revascularization strategies in
      patients with PE is to reduce the thrombus load in pulmonary arteries, thereby reversing
      right ventricular dysfunction improving symptoms and survival.9 Reperfusion strategies
      encompass catheter-directed thrombolysis and surgical embolectomy and should be considered in
      selected high and intermediate-high-risk patients with PE.

      According to current guidelines of the European Society of Cardiology (ESC) published in
      20146 catheter-directed treatment (Grade 2aC) or surgical embolectomy (Grade 1C) should be
      considered in all patients with PE at high risk, in whom systemic thrombolytic therapy is
      contraindicated or has failed. Also, catheter-directed treatment (Grade 2bB) or surgical
      embolectomy (Grade 2bC) may be considered in intermediate-high-risk patients with PE.
      However, it remains unclear, which reperfusion strategy is most appropriate for high and
      intermediate-high-risk patients with PE.

      Catheter-directed Thrombolysis Given, that anticoagulation alone has little effect on
      improvement of RV performance in the early phase, catheter-directed thrombolysis appears to
      be effective for early RV recovery.10 There are two main approaches for catheter-directed
      thrombolysis, i.e., conventional catheter-directed thrombolysis and pharmacomechanical
      thrombolysis.

      Conventional catheter-directed thrombolysis:

      Thrombolytic agents, for example, recombinant tissue plasminogen activator (rtPA) at a dose
      of 1-2mg per hour for up to 24 hours, are infused through side-hole catheters which are
      placed at the side of the thrombotic occlusion in the pulmonary arteries.

      Pharmacomechanical thrombolysis:

      Pharmacomechanical thrombolysis refers to catheter-directed thrombolysis combined with a
      mechanical catheter technique. In addition to the thrombectomy mode, the AngioJet® system
      (Boston Scientific, USA) enables a high-pressure intraclot injection of thrombolytic agents
      (PowerPulse® technique). Ultrasound-assisted thrombolysis is another type of
      pharmacomechanical thrombolysis which aims to accelerate thrombolysis success. It consists of
      a thrombolysis catheter with a microsonic core wire that uses high-frequency low-power
      ultrasound waves (EKOS Corporation; Bothell, WA, USA).

      In a randomized, controlled clinical trial of 59 intermediate-risk patients ultrasound
      assisted catheter-directed- thrombolysis significantly reduced RV-LV ratio after 24 hours
      compared to heparin alone without an increase in bleeding rates.11 In the present trial,
      pharmacomechanical thrombolysis will be used in the catheter therapy group.

      Surgical Pulmonary Embolectomy Historically and according to current guidelines, surgical
      embolectomy (SE) is reserved for patients in whom thrombolysis was contraindicated or had
      failed. Therefore the majority of SE were performed in critically ill patients, resulting in
      high mortality rates.12 Recent publications including our own experience reported reduced
      mortality rates even in patients with cardiac arrest and preoperative cardiopulmonary
      resuscitation13. Many authors question the restrictive role of SE compared to systemic
      thrombolytic therapy and advocate SE in hemodynamically stable patients with signs of RV
      Dysfunction and high clot burden in the central pulmonary artery.

      Surgical embolectomy (SE) is performed though a median sternotomy using mild hypothermic or
      normothermic cardiopulmonary bypass (CPB). The main pulmonary artery is opened with a
      longitudinal incision, which can be extended into the right and left pulmonary artery
      branches. The thrombotic material is extracted using a special forceps and by assisting
      suction. To ensure complete clot removal the right and left pulmonary artery branches a
      flexible surgical angioscope can be used to inspect the segmental arteries. Massage of the
      lungs is not performed to avoid additional damage to the lung parenchyma. The right atrium
      and ventricle are routinely explored, all clot material is carefully removed and a patent
      foramen ovale if present is closed with a 4-0 running suture. The pulmonary arteriotomy is
      closed with a running suture, and the patient is weaned from CBP after declamping of the
      aorta. The patient is transferred to the intensive care unit and is treated with intravenous
      unfractioned heparin (initial dosage of 1000Ul/24h, the goal is to achieve an activated
      partial thromboplastin-time ratio of at least twice the control value) starting six hours
      after surgery. All patients receive in the follow-up period oral anticoagulation with
      warfarin (starting on postoperative day one) with an International Normalized Ratio (INR)
      target of 2.5± 0.5 for at least 3 months.
    

Intervention name(s): surgical pulmonary embolectomy; catheter-directed thrombolysis
Intervention type(s): Procedure; Combination Product
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Monocentric, randomized, open-label, controlled, clinical, non-inferiority trial.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: surgical embolectomy; catheter-directed therapy