Clinical Surveillance vs. Anticoagulation for Low-risk Patients With Isolated Subsegmental Pulmonary Embolism (SAFE-SSPE)

Clinical Surveillance vs. Anticoagulation for Low-risk Patients With Isolated Subsegmental Pulmonary Embolism: a Multicenter Randomized Placebo-controlled Non-inferiority Trial

The clinical significance of pulmonary embolism (PE) limited to the subsegmental pulmonary arteries, so called isolated subsegmental pulmonary embolism (SSPE), remains controversial. Whether isolated SSPE represents "true" PE, a clinically more benign form of PE, a physiologic lung clearing process, or a false positive result (artifact) is currently unclear and hence, whether patients with isolated SSPE benefit from anticoagulant treatment is uncertain. Despite growing evidence from observational studies that withholding anticoagulation may be a safe option in selected patients with isolated SSPE (i.e., those without concomitant deep vein thrombosis, cancer, etc.), most patients with isolated SSPE receive anticoagulant treatment, which is associated with an increased risk of bleeding. The overall objective of the randomized controlled SAFE-SSPE trial is to evaluate the efficacy and safety of clinical surveillance without anticoagulation compared to anticoagulation treatment in low-risk patients with isolated SSPE.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism; Embolism and Thrombosis; Bleeding; Venous Thromboembolism; Pulmonary Embolism; Anticoagulant-induced Bleeding
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 276
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Drahomir Aujesky, Prof. MD MSc; Phone Number: +41 31 632 88 84; Email: SAFE-SSPE@insel.ch
• Study Contact Backup: Name: Tobias Tritschler, Dr. MD MSc; Phone Number: +41 31 63 2 01 46; Email: SAFE-SSPE@insel.ch

Study Locations

• Canada
  • Ottawa, Canada
    • Recruiting
    • The Ottawa Hospital
    • Contact: Marc Carrier, Prof. MD MSc
• France
  • Brest, France
    • Recruiting
    • Centre Hospitalier Régional et Universitaire de Brest
    • Contact: Francis Couturaud, Prof. MD
• Netherlands
  • Den Haag, Netherlands
    • Recruiting
    • Haaglanden Medisch Centrum
    • Contact: H.M. A. Hofstee, MD
  • Dordrecht, Netherlands
    • Recruiting
    • Albert Schweitzer Ziekenhuis Dordrecht
    • Contact: P.E. Westerweel, MD
  • Enschede, Netherlands
    • Recruiting
    • Medisch Spectrum Twente
    • Contact: H.P.A.A. van Veen, MD
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center
    • Contact: F. A. Klok, Prof. MD PhD
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Universitair Medisch Centrum
    • Contact: M. Kruip, MD
  • Zwolle, Netherlands
    • Recruiting
    • Isala Klinieken Zwolle
    • Contact: M. F. Boosma, MD
• Switzerland
  • Baden, Switzerland
    • Recruiting
    • Cantonal hospital of Baden
    • Contact: Maria Wertli, Prof. MD
  • Basel, Switzerland
    • Recruiting
    • University Hospital of Basel
    • Contact: Roland Bingisser, Prof. MD
  • Bern, Switzerland, 3010
    • Recruiting
    • University Hospital Inselspital
    • Contact: Drahomir Aujesky, Prof. MD MSc
  • Bern, Switzerland
    • Recruiting
    • Tiefenau Hospital
    • Contact: Manfred Essig, Prof. MD
  • Burgdorf, Switzerland
    • Recruiting
    • Regional Hospital of Emmental
    • Contact: Robert Escher, PD Dr. MD
  • Delémont, Switzerland
    • Recruiting
    • Hospital of Delémont
    • Contact: Hervé Duplain, PD Dr. MD
  • Fribourg, Switzerland
    • Recruiting
    • Cantonal Hospital of Fribourg
    • Contact: Julien Vaucher, Prof. MD
  • Geneva, Switzerland
    • Recruiting
    • Geneva University Hospital
    • Contact: Marc Righini, Prof. MD
  • Lucerne, Switzerland
    • Recruiting
    • Cantonal Hospital of Lucerne
    • Contact: Christoph Henzen, Prof. MD
  • Neuchâtel, Switzerland
    • Recruiting
    • Hospital of Neuchâtel
    • Contact: Jacques Donzé, Prof. MD MSc
  • Zürich, Switzerland
    • Recruiting
    • University Hospital Zurich
    • Contact: Ksenija Slankamenac, PD, MD, PhD
  • Zürich, Switzerland
    • Recruiting
    • Triemli Hospital
    • Contact: Lars Huber, PD MD
  • Aargau
    • Aarau, Aargau, Switzerland
      • Recruiting
      • Cantonal Hospital of Aarau
      • Contact: Philippe Schütz, Prof. MD MPH
  • Basel
    • Liestal, Basel, Switzerland
      • Recruiting
      • Cantonal Hospital of Liestal
      • Contact: Jörg Leuppi, Prof. MD PhD
  • Bern
    • Bienne, Bern, Switzerland
      • Recruiting
      • Hospital of Bienne
      • Contact: Daniel Genné, Prof. MD
  • Saint Gallen
    • St. Gallen, Saint Gallen, Switzerland
      • Recruiting
      • Cantonal Hospital of St. Gallen
      • Contact: Claudio S. Rüegg, MD
  • Solothurn
    • Olten, Solothurn, Switzerland
      • Recruiting
      • Cantonal Hospital of Olten
      • Contact: Lukas Zimmerli, PD MD EMBA
  • Thurgau
    • Frauenfeld, Thurgau, Switzerland
      • Recruiting
      • Cantonal Hospital of Frauenfeld
      • Contact: Andreas Kistler, PD MD
  • Valais
    • Sion, Valais, Switzerland
      • Recruiting
      • Hospital of Sion
      • Contact: Pierre-Auguste Petignat, Prof. MD
  • Vaud
    • Lausanne, Vaud, Switzerland
      • Recruiting
      • University Hospital of Lausanne
      • Contact: Marie Méan, MD MER
    • Nyon, Vaud, Switzerland
      • Recruiting
      • Hospital of Nyon
      • Contact: Mallory Moret Bochatay, MD
  • Zurich
    • Winterthur, Zurich, Switzerland
      • Recruiting
      • Cantonal Hospital of Winterthur
      • Contact: Reinhard Imoberdorf, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Informed Consent as documented by signature
2. Age ≥18 years
3. Objective diagnosis of symptomatic or asymptomatic isolated SSPE

Exclusion Criteria:

1. Presence of leg deep vein thrombosis (DVT) or upper extremity DVT (subclavian vein or above)
2. Active cancer, defined as cancer treated with surgery, chemotherapy, radiotherapy, or palliative care during the last 6 months
3. ≥1 prior episode of unprovoked VTE (absence of a transient or permanent risk factor)
4. Clinical instability (systolic blood pressure <100 mm Hg or arterial Oxygen saturation <92% at ambient air) at the time of presentation
5. Active bleeding or at high risk of bleeding
6. Severe renal failure (creatinine clearance <30ml/min)
7. Severe liver insufficiency (Child-Pugh B or C)
8. Concomitant use of strong CYP3A4 inhibitors or strong CYP3A4 inducers
9. Known hypersensitivity to rivaroxaban
10. Need for therapeutic anticoagulation for another reason
11. Therapeutic anticoagulation for >72 hours for any reason at the time of screening
12. Hospitalized for >72 hours prior to the diagnosis of isolated SSP (hospital-acquired VTE)
13. Known pregnancy or breast feeding (pregnancy test to be performed for women of childbearing potential)
14. Lack of safe contraception in women of childbearing potential
15. Refusal or inability to provide informed consent
16. Prior enrolment in this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Anticoagulation; Patients in the anticoagulation group will receive rivaroxaban 15 mg twice daily for the first 21 days, followed by 20 mg once daily for an overall treatment duration of 90 days.	Drug: Rivaroxaban; Anticoagulation
Placebo Comparator: No anticoagulation; Patients in the group without anticoagulation will receive placebo twice daily for the first 21 days, followed by one tablet daily for an overall treatment duration of 90 days.	Drug: Placebo; Study drug without active agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrent venous thromboembolism	Proportion of recurrent, clinically symptomatic, objectively confirmed venous thromboembolism (defined as recurrent fatal or nonfatal pulmonary embolism or lower limb deep vein thrombosis)	Within 90 days of randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinically significant bleeding	Proportion of the composite of major and clinically relevant non-major bleeding	Within 90 days of randomization
All-cause mortality	Proportion of deaths (all causes of death will be considered)	Within 90 days of randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health-related quality of life	Pulmonary embolism related quality of life as assessed by the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire	Within 90 days of randomization
Functional status	Functional status as assessed by the post-venous thromboembolism functional status scale	Within 90 days of randomization
Initial length of stay (LOS)	Defined as the time/date of discharge minus time/date of admission at the emergency department	Within 90 days of randomization
Subsequent overall hospitalizations	Number of overall hospitalizations	Within 90 days of randomization
Emergency departments and physician outpatient visits	Number of emergency department and physician outpatient visits	Within 90 days of randomization
Return to work or usual activities	Time (days) to return to work in workers and usual activities (household) in non-workers	Within 90 days of randomization

Collaborators and Investigators

• Sponsor: Drahomir Aujesky
• Collaborators: Bayer; The Ottawa Hospital; University of Bern; Leiden University Medical Center; Schweizerischer Nationalfonds
• Investigators: Study Director: Drahomir Aujesky, Prof. MD MSc, Inselspital, Bern University Hospital, University of Bern

Publications and helpful links

General Publications

• Baumgartner C, Klok FA, Carrier M, Limacher A, Moor J, Righini M, Beer JH, Peluso M, Rakovic D, Huisman MV, Aujesky D. Clinical Surveillance vs. Anticoagulation For low-risk patiEnts with isolated SubSegmental Pulmonary Embolism: protocol for a multicentre randomised placebo-controlled non-inferiority trial (SAFE-SSPE). BMJ Open. 2020 Nov 19;10(11):e040151. doi: 10.1136/bmjopen-2020-040151.

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2020
• Primary Completion (Estimated): February 1, 2024
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: February 4, 2020
• First Submitted That Met QC Criteria: February 6, 2020
• First Posted (Actual): February 10, 2020

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 27, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: subsegmental pulmonary embolism
• Additional Relevant MeSH Terms: Pathologic Processes; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Embolism; Hemorrhage; Thrombosis; Thromboembolism; Venous Thromboembolism; Pulmonary Embolism; Respiratory Tract Diseases; Embolism and Thrombosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: 2019-02297

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After publication of the study results, a de-identified patient-level data set relating to the primary publication along with the latest version of the study protocol, the informed consent form, the statistical analysis plan, the code used for the analyses, and the Data Management and Quality Plan describing all data management aspects of the study will be made publicly available for replication of the study results and secondary data analyses in the Bern Open Repository and Information System (BORIS) Research Data, an online non-commercial data repository that meets Swiss National Science Foundation requirements for FAIR Data Principles (www.force11.org/group/fairgroup/fairprinciples)
• IPD Sharing Time Frame: After publication of the study results
• IPD Sharing Access Criteria: Data will be publicly available for replication of the study results and secondary data analyses in the Bern Open Repository and Information System (BORIS) Research Data
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No