Surgical Pulmonary Embolectomy Versus Catheter-directed Thrombolysis in the Treatment of Pulmonary Embolism: A Non-inferiority Study
Surgical Pulmonary Embolectomy Versus Catheter-directed Thrombolysis in the Treatment of Pulmonary Embolism: A Non-inferiority Study
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.
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.
Inclusion Criteria:

 1. Acute symptomatic PE with thrombus located in the pulmonary main trunk or the left
 and/or right main pulmonary artery

 2. High-risk PE defined as PE with sustained systemic arterial hypotension (systolic
 pressure <90mmHg), cardiogenic shock, or the ongoing need for catecholamine therapy

 OR

 Intermediate-high risk PE: Imaging evidence of RV-Dilatation (right-to-left
 ventricular diameter ratio >1.0 on echocardiography or chest computed tomography) and
 biomarker evidence of RV dysfunction (positive Troponin T or I Test).

 3. The eligibility for both procedures must be established by the PERT team

 4. Signed Informed consent (by subject or legal representative) -

 Exclusion Criteria:

 1. Age less than 18 years or greater than 80 years.

 2. Symptom duration > 14 days suggesting acute-on-chronic pulmonary embolism.

 3. Known chronic thromboembolic pulmonary hypertension (CTEPH)

 4. Suspected chronic thromboembolic pulmonary hypertension (CTEPH) including RV
 hypertrophy (RV free wall >5 mm on echocardiography), severe pulmonary hypertension
 (systolic pulmonary artery pressure > 80 mmHg on echocardiography), or CT findings
 suggestive of CTEPH including intraluminal webs, bands, strictures, or eccentric
 filling defects adjacent to the wall of the pulmonary arteries

 5. Decompensated cardiogenic shock defined as recent (<48 hours) cardiopulmonary
 resuscitation therapy or worsening hemodynamic status despite extended fluid and
 catecholamine support

 6. Inability to tolerate catheter procedure or surgical embolectomy due to severe
 comorbidities.

 7. Allergy, hypersensitivity, or thrombocytopenia from heparin, r-tPA, or iodinated
 contrast, except for mild-moderate contrast allergies for which steroid pre-medication
 can be used.

 8. Known significant bleeding risk, or known coagulation disorder (including vitamin K
 antagonists with INR > 2.0 and platelet count < 100 000/mm3)

 9. Severe renal impairment (estimated GFR < 30 ml/min).

 10. Active bleeding: recent (< 3 months) GI bleeding, severe liver dysfunction, bleeding
 diathesis.

 11. Recent (< 3 months) internal eye surgery or hemorrhagic retinopathy; recent (< 10
 days) major surgery, cataract surgery, trauma, CPR, obstetrical delivery, or other
 invasive procedure.

 12. History of stroke or intracranial/intraspinal bleed, tumor, vascular malformation,
 aneurysm.

 13. Severe hypertension on repeated readings (systolic > 180 mmHg or diastolic > 105
 mmHg).

 14. Pregnant, lactation or parturition within the previous 30 days (positive pregnancy
 test in women of childbearing age)

 15. Recent (< 1 month) systemic thrombolysis.

 16. Life expectancy < 6 months or chronic non-ambulatory status.

 17. Participating in any other investigational drug or device study or previous enrollment
 in this study

 18. Inability to comply with study assessments (e.g. due to cognitive impairment or
 geographic distance).

 19. Any other condition that the investigator feels would place the patient at increased
 risk if the investigational therapy is initiated.