STOPping Anticoagulation for Isolated or Incidental Subsegmental Pulmonary Embolism

Study Overview
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Brief Summary
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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.

Official Title
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STOPping Anticoagulation for Isolated or Incidental Subsegmental Pulmonary Embolism

Conditions
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Subsegmental Pulmonary Embolism Nos

Intervention / Treatment
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* Other: No treatment
* Drug: Warfarin
* Drug: direct oral anticoagulants
* Drug: Low molecular weight heparin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |