STOPping Anticoagulation for Isolated or Incidental Subsegmental Pulmonary Embolism (STOPAPE)

Pulmonary embolisms (PE) occur when blood clots cause a blockage of the blood supply to the lungs. A small PE located in the subsegmental pulmonary vasculature is identified as a subsegmental PE (SSPE). Anticoagulants are used to treat SSPE and work by preventing new clots from forming whilst the body's own mechanisms break down the clots, however they can also increase the risk of major and potentially life threatening bleeding. More recent observational data of routine care for SSPE showed very high complication rates of anticoagulation but in patients where treatment was withheld, this proved to be a safe strategy in terms of recurrent venous thromboembolism (VTE).

Computed tomography pulmonary angiography (CTPA) scans are now able to detect SSPE, however there are concerns that there is an over-diagnosis due to the incorrect interpretation of small artefacts. 1466 patients from approximately 50 sites will be recruited, these sites will consist of hospitals across the United Kingdom (UK). Patients 18 and over with isolated SSPE, confirmed by either CTPA or CT thorax with IV contrast, will be eligible for the trial. Patients will be randomised to either receive standard anticoagulation for at least 3 months (control) or no anticoagulation for at least 3 months (intervention). The participant will receive telephone follow up calls at 4, 12 and 24 weeks following the end of their treatment, and additional data will also be taken from their medical records at these time points. The participant isn't required to be contacted for the 52 week follow up as the data will be extracted from the National Health Service (NHS) Digital collection of Hospital Episode Statistics (HES). In total participation in the study will last 12 months. In addition the cost-effectiveness of no treatment versus treatment with full anticoagulation will be looked at and also improving on radiological diagnosis of SSPE.

Study Overview

• Status: Recruiting
• Conditions: Subsegmental Pulmonary Embolism Nos
• Intervention / Treatment: Drug: Warfarin; Drug: direct oral anticoagulants; Drug: Low molecular weight heparin; Other: No treatment

• Study Type: Interventional
• Enrollment (Anticipated): 1466
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Pooja Gaddu; Phone Number: 01214159120; Email: p.gaddu@bham.ac.uk

Study Locations

• United Kingdom
  • Redhill, United Kingdom, RH1 5RH
    • Recruiting
    • Surrey & Sussex Healthcare NHS Trust
    • Contact: Sarah Davies; Phone Number: 2804 01737 768511; Email: sarah.davies60@nhs.net
    • Principal Investigator: Jenny Bacon

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥18 years
• SSPE diagnosed by the radiologist at the trial site by CTPA or CT thorax with IV contrast
• No evidence of proximal deep vein thrombosis on doppler ultrasonography or CT / Magnetic Resonance venography
• Heart rate (<110bpm)
• Systolic blood pressure (≥100 mmHg)
• Oxygen saturation (≥90%)
• Written signed informed consent to the trial

Exclusion Criteria:

• Indication for hospital admission
• >7 days empirical anticoagulation treatment immediately prior to randomisation
• <28 days since first symptoms of proven or clinically suspected Coronavirus disease (COVID-19)
• Known stage 5 chronic kidney disease
• Patients with active cancer defined as cancer diagnosed within the past 6 months, cancer for which anticancer treatment was being given at the time of enrolment or during 6 months before randomisation, or recurrent locally advanced or metastatic cancer
• Patients with previous unprovoked PE, thrombophilia or requiring long term anticoagulation for another reason
• Patients with a Deep Vein Thrombosis / thrombus of an unusual site (e.g. upper limbs, associated with a line) that requires anticoagulation
• Patients with active bleeding
• Any condition which, in the opinion of the investigator, makes the participant unsuitable for trial entry due to prognosis/terminal illness with a projected survival of less than 3 months
• Pregnancy confirmed by positive pregnancy test or post-partum period or actively trying to conceive
• Inability to comply with the trial schedule and follow-up
• Participation in a Clinical Trial of Investigative Medicinal Product (CTIMP) study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; Full dose anticoagulation treatment as standard care for at least 3 months.	Drug: Warfarin; anticoagulation drug given for at least 3 months.; Drug: direct oral anticoagulants; anticoagulation drug given for at least 3 months.; Drug: Low molecular weight heparin; anticoagulation drug, subcutaneous injection given for at least 3 months.
Experimental: Intervention; Withholding anticoagulation for Isolated Sub-Segmental Pulmonary Embolism (ISSPE) for at least 3 months.	Other: No treatment; Withholding anticoagulation for at least 3 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A composite score of the number of recurrent venous thromboembolism and/or clinically relevant bleeding	To determine if withholding anticoagulation is non-inferior to standard anticoagulation therapy in the treatment of isolated or incidental subsegmental pulmonary embolism for preventing recurrent venous thromboembolism, and/or death related and non death related venous thromboembolism, or superior for clinically relevant bleeding over 3 months, compared with at least 3 months of full anticoagulation. This will be measured using a scoring system which is currently being developed by the statistical team, and will be detailed in the statistical analysis plan when finalised.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in frequency and severity of harmful events	Determine whether withholding anticoagulation for isolated subsegmental pulmonary embolism reduces harmful events (recurrent venous thromboembolism, clinically relevant bleeding) compared with at least 3 months of full anticoagulation at 6 and 12 months. This will be assessed through Hospital Episode Statistic records.	6 and 12 months
Number of new diagnosis of pulmonary hypertension of right ventricular dysfunction identified from Hospital Episode Statistics.	Determine the impact of withholding anticoagulation for isolated subsegmental pulmonary embolism on diagnoses of pulmonary hypertension at 12 months. Measure new diagnosis of pulmonary hypertension or right ventricular dysfunction within 12 months of subsegmental pulmonary embolism, defined from Hospital Episode Statistics clinical coding and supported where possible by additional radiological data and echocardiogram undertaken in tertiary pulmonary hypertension centres. The parameters and variables used to analysed data from the Hospital Episode Statistics are being developed and will be outlined in the statistical analysis plan when finalised.	12 months
Reclassification rate from thoracic radiologist review	Determine the reclassification rate of subsegmental pulmonary embolism diagnoses made by acute reporting radiologists when reviewed by thoracic radiologists and formulate a set of rules to improve acute reporting radiologists' diagnoses of subsegmental pulmonary embolism.	32 months
Measuring the rate of net clinical benefit	A composite of clinically relevant bleeding and recurrent venous thromboembolism at 3 and 6 months, measured at the 3 and 6 month follow up time points using statistical coding as described in the statistical analysis plan.	3 and 6 months
Measuring the rate of mortality	Measurement of all-cause mortality and venous thromboembolism related mortality at 3, 6 and 12 months. Measurement of cardiovascular mortality at 3, 6 and 12 months defined as cardiac deaths (e.g. cardiogenic shock, fatal arrhythmia, cardiac rupture) and vascular deaths (e.g. venous thromboembolism related, fatal stroke, ruptured aortic aneurysm, aortic dissection).	3, 6 and 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Healthcare resource use and cost	An economic evaluation will be undertaken to assess the cost-effectiveness of no treatment versus full dose anticoagulation in patients with isolated or incidental subsegmental pulmonary embolism. The base-case evaluation will take the form of an incremental cost-utility analysis to estimate cost per quality adjusted life year (QALY) over a 24 week follow up period using a version of the EuroQol descriptive questionnaire (EQ-5 Dimensions -5Levels), and a cost-effectiveness analysis to estimate cost per venous thromboembolism avoided over 52 weeks using routine data sources. Both analyses will be from a health services perspective. Additional analysis, using decision modelling, will explore the cost utility and cost-effectiveness of a pragmatic treatment policy (without expert thoracic radiological review) over a 52 week time horizon.	12 months
Behavioural analysis of the participants	To determine whether not treating subsegmental pulmonary embolism is acceptable to patients. To determine the health seeking behaviours and health utilisation of a no anticoagulation treatment strategy for isolated or incidental subsegmental pulmonary embolism. Selected patients will be interviewed by the qualitative researchers using a pre-set interview schedule via telephone or video calls.	32 months
Behavioural analysis of the healthcare professionals	To determine whether not treating subsegmental pulmonary embolism is acceptable to healthcare professionals. To determine the health seeking behaviours and health utilisation of a no anticoagulation treatment strategy for isolated subsegmental pulmonary embolism. Selected healthcare professionals will be interviewed by the qualitative researchers using a pre-set interview schedule via telephone or video calls.	32 months

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: Royal United Hospitals Bath NHS Foundation Trust; Cimar

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2021
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): May 1, 2024

Study Registration Dates

• First Submitted: January 7, 2021
• First Submitted That Met QC Criteria: January 25, 2021
• First Posted (Actual): January 27, 2021

Study Record Updates

• Last Update Posted (Actual): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Heparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Warfarin; Anticoagulants
• Other Study ID Numbers: Worktribe 799297; 280586 (Other Identifier: IRAS); ISRCTN15645679 (Other Identifier: ISRCTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

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