Award Title: Stopping anticoagulation for isolated or incidental sub-segmental pulmonary embolism (STOPAPE)
Funder: Department of Health and Social Care

Abstract: Pulmonary embolism (PE) is a potentially serious condition, whereby blood clots cause a blockage of the blood supply to the lungs.  PEs are often caused by blood clots in the legs and occasionally the arms (deep vein thrombosis (DVT)) breaking off and travelling to the lungs.  A number of risk factors increase the chances of developing PE and/or DVT, including cancer, major surgery, pregnancy, some medications (e.g. the combined oral contraceptive pill or hormone replacement therapy), dehydration, long-distance travel and prolonged immobility.  The symptoms of a PE depend on the size and location of the blood clot.  A large PE can cause symptoms of breathlessness and chest pain, and the diagnosis is made using blood tests and a scan of the lungs.  The treatment of PE includes anticoagulant medication (“blood thinners”) that are taken over months and include: warfarin, an injectable form of heparin and direct oral anticoagulants (DOACs).  These medications work by preventing new clots from forming whilst the body’s own mechanisms break down the clots._x000D_
_x000D_
As the scanning technology for PE has become more sensitive, smaller clots are being diagnosed. In addition, small PEs may not cause any symptoms and may be found incidentally on scans performed for other reasons.  In these situations, it is unclear whether treatment is required for the PE.  These clots in smaller blood vessels away from the centre of the lungs (subsegmental PE) may be removed by the body’s own mechanisms for dissolving clots without needing medications.  Anticoagulant medication can cause side effects in some patients such as bleeding.  For the anticoagulant medication to be appropriate in these smaller PEs the benefits from preventing future blood clots (PEs and DVTs) would need to outweigh the potential risks from the medication side effects.  The study aims to address this question.  _x000D_
_x000D_
This trial will enrol 1466 patients who have an isolated or incidental subsegmental PE confirmed on CT scanning of the chest, and are well enough to not need ongoing treatment in hospital. Patients will have an equal chance of receiving the current standard of care (anticoagulant medication) or no anticoagulant treatment for at least 3 months.  Follow-up by the researchers will occur for up to 6 months, with further data collection until at least 12 months using routine NHS records. We will assess patient and staff perceptions of the risks and benefits of not providing anticoagulant medication in these types of PEs, by conducting interviews with up to 60 people.  Additionally, we will assess how cost-effective the no treatment approach is and perform a safety analysis after 3 months of follow-up._x000D_
_x000D_
Our team includes a patient with experience of blood clots (CR) and a thrombosis expert (SN) who are project officer and medical director of Thrombosis UK respectively, the UK’s leading thrombosis charity. This link with Thrombosis UK will ensure our study is feasible and of relevance to patients, as well as helping us spread the findings through their established communications network. The study team has experience of conducting clinical trials in hospitals, as well as those which enrol patients taking blood thinning treatment. We have designed this study alongside a local patient group who will also remain involved for their views throughout the study.  We anticipate the study will be completed in four and a half years.

Lay Abstract: Research Question: Is withholding anticoagulation for patients with isolated subsegmental pulmonary embolism (SSPE) clinically and cost effective compared with full anticoagulation for three months?_x000D_
Background: The increasing use of computed tomography pulmonary angiography (CTPA) to investigate patients with suspected pulmonary embolism (PE) has led to an increase in the diagnosis of SSPE. The decreased case fatality rate for PE together with an increase in SSPE incidence suggests overdiagnosis and questions the need for anticoagulation treatment in SSPE. There is growing equipoise about the value of full anticoagulation for patients with SSPE who do not have an associated proximal deep vein thrombosis, given the significant side effects of bleeding and the insufficient evidence of improved mortality or reduced VTE recurrence with treatment._x000D_
Objectives: _x000D_
1. Determine whether or not anticoagulating for incidental/subsegmental PE reduces harm (recurrent VTE and bleeding events) compared with three months of full anticoagulation at 3, 6 and 12 months _x000D_
2. Determine the rate of complications of anticoagulation therapy in patients with SSPE. _x000D_
3. Determine whether not treating SSPE is acceptable to patients and clinicians_x000D_
4. Determine the reclassification rate of SSPE diagnoses made by acute reporting radiologists when reviewed by thoracic radiologists and formulate a set of rules to improve acute reporting radiologists' diagnoses of SSPE._x000D_
5. Assess cost-effectiveness of the no treatment approach in patients with SSPE, taking a health service perspective._x000D_
6. Set up an acute PE research network to support follow on research studies._x000D_
Methods: Individual patient randomised open controlled trial with blinded committee adjudicated end point assessment, powered for superiority for bleeding events and non-inferiority for recurrent venous thromboembolism (VTE), including an internal pilot for feasibility and acceptability of the intervention (no anticoagulation). In order to demonstrate non-inferiority for the outcome of recurrent VTE in patients randomised to no anticoagulation at an upper margin of 2.5%, we require 1466 patients which allows for a 10% drop out rate. Superiority for bleeding events in the no anticoagulation arm is needed to change practice and 1338 patients (allowing for 10% drop out) will give us 90% power to detect a reduction in bleeding events (major and CRNMB) from 7% in the anticoagulation arm to 3% in the intervention arm. Our planned recruitment of 1466 patients over a 32 month window from 50 sites, opening 2 new sites per month, ensures we are powered for both outcomes._x000D_
A nested study of all CTPAs will be performed, comparing the SSPE diagnosis made by the acute reporting radiologists with specialist thoracic radiologists. This will allow us to determine safety in the pilot study (patients with larger than subsegmental clot are rapidly identified), appropriate powering and sample size (e.g. patients with breathing artefact may be recruited instead of true SSPE) and develop guidance for SSPE diagnosis in routine clinical practice._x000D_
Timelines: 54 months, with a 12 month internal pilot _x000D_
Impact: If the trial results are positive, this will change National Institute for Health and Care Excellence and British Thoracic Society guidance for VTE treatment.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: BLOOD