A trial to determine if withholding anticoagulation is not worse than standard anticoagulation therapy in the treatment of blood clots in the lungs
| ISRCTN | ISRCTN15645679 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15645679 |
| IRAS number | 280586 |
| ClinicalTrials.gov number | NCT04727437 |
| Secondary identifying numbers | CPMS 46105, IRAS 280586 |
- Submission date
- 24/09/2020
- Registration date
- 23/10/2020
- Last edited
- 28/02/2025
- Recruitment status
- Stopped
- Overall study status
- Stopped
- Condition category
- Circulatory System
Plain English Summary
Background and study aims
Pulmonary embolism (PE) is a condition where blood clots cause a blockage of the blood vessels in the lungs. PEs are often caused by blood clots in the legs (deep vein thrombosis [DVT]) breaking off and travelling to the lungs. The symptoms of a PE depend on the size and location of the blood clot and can include breathlessness and chest discomfort. The standard treatment for PE includes anticoagulant drugs commonly referred to as “blood thinners”. Anticoagulants include a drug called warfarin, direct oral anticoagulant (DOACs) tablets, or a type of drug called “low molecular weight heparin” that is injected under the skin. These drugs stop new clots from forming while the body breaks down clots that may have already formed. A PE is diagnosed by a scan of the lungs, which is most commonly a computed tomography pulmonary angiogram (CTPA). This gives doctors images of the pulmonary arteries, a small PE in these blood vessels is called a “subsegmental pulmonary embolism” (SSPE).
As the CTPA scanning technology for PE has become more sensitive, smaller clots are being diagnosed. The CTPA scans are now able to detect smaller blood clots in blood vessels of the lungs; these clots are only a few millimetres in size and are the subsegmental pulmonary embolisms (SSPE).
The current standard treatment for pulmonary embolism is anticoagulant drugs. The aim is to reduce future blood clots (PEs and DVTs). It is unclear if the smaller clots, the SSPEs, require treatment with anticoagulation as these smaller PEs may be broken down by the body itself without the need for any treatment. Patients with SSPE who are treated with anticoagulation could be more at harm due to the risk of bleeding than they are helped by preventing future blood clots. This study will compare the outcomes among people with SSPE who have no anticoagulation treatment with those that are anticoagulated. The results of this will help us find out which is the best treatment plan for patients with SSPE.
Who can participate?
Patients aged 18 and older with a subsegmental pulmonary embolism
What does the study involve?
Participants are randomly allocated to either continue with standard anticoagulation or to have no anticoagulation treatment at all and are assessed after 12, 24 and 52 weeks.
What are the possible benefits and risks of participating?
Although participants may not receive any individual benefit from taking part in the study, the results may help to improve the treatment of patients with SSPE in the future. If the participant is allocated to have anti-coagulation treatment then the potential risks are the same as usual care which will have already been discussed with the participant. The participant may experience bleeding from the anticoagulants, which can be minor like a small nose bleed or sometimes more severe (where the participant might need to come to hospital to have a blood transfusion). If the participant is allocated to the no treatment group then they are less likely to have either bleeding as they will not be on anticoagulants, but they may get another blood clot in the lungs (PE) or legs (DVT). The participant will be given a patient card that explains the symptoms to look out for which should prompt them to seek healthcare in case they have had another PE or DVT.
Where is the study run from?
University of Birmingham (UK)
When is the study starting and how long is it expected to run for?
October 2019 to March 2024
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
Pooja Gaddu
stopape@trials.bham.ac.uk
Contact information
Scientific
Birmingham Clinical Trials Unit
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0)121 415 9120 |
|---|---|
| stopape@trials.bham.ac.uk |
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Diagnosis, Drug, Management of Care |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Available at https://www.birmingham.ac.uk/stop-ape |
| Scientific title | STOPping Anticoagulation for isolated or incidental subsegmental Pulmonary Embolism |
| Study acronym | STOP-APE |
| Study hypothesis | To determine if withholding anticoagulation is non-inferior to standard anticoagulation therapy in the treatment of isolated subsegmental pulmonary embolism (ISSPE) for preventing recurrent venous thromboembolism (VTE), or death related VTE, or superior for clinically relevant bleeding over 3 months, compared with at least 3 months of full anticoagulation. |
| Ethics approval(s) | Approved 30/09/2020, Wales REC 6 (c/o Public Health Wales, Building 1, Jobswell Road, St David’s Park, SA31 3HB, UK; +44 (0)1267 61 1164; Wales.REC6@wales.nhs.uk), REC ref: 20/WA/0256 |
| Condition | Isolated or incidental subsegmental pulmonary embolism |
| Intervention | The design is a prospective randomised open blinded end point (PROBE) trial, with individual level randomisation. The researchers have used an open design because of the importance of understanding how the knowledge of a diagnosis of SSPE yet being sent home without anticoagulation affects health seeking behaviour. This would be the situation in real clinical practice, were the results of the trial to support no anticoagulation. If the researchers had opted for a placebo-controlled trial they would not be able to predict the impact of the management strategy in routine practice. An internal pilot (first 12 months of recruitment) will inform progression criteria to the main trial and a nested study of diagnostic accuracy will ensure safety for participants. Process evaluation: The researchers will focus on acceptability and the potential consequences of a no treatment approach, through conducting interviews with a range of patients (n=30) and healthcare professionals (HCP; n=30). The topic guide will be developed drawing on existing literature on reporting of, attitudes to, and outcomes from incidental diagnoses. The researchers will explore attitudes and practical issues surrounding tolerance of risk by patients and HCPs. If having a PE and knowingly not being treated changes how one responds to transient symptoms (e.g. leg or chest pain) then a potential outcome may be excess scans and emergency presentations in the untreated group. Distress at receiving a diagnosis of VTE, particularly as an incidental finding and the harm of repeated diagnostic imaging in this context will therefore be important to assess. Interviews will be audio recorded and transcribed verbatim, prior to qualitative analysis using the framework method. If patient/health care professional consents to this they will be interviewed by a researcher at a place that is convenient for them, either face-to-face in their own home or a hospital site, or by telephone/video call. The interview will take around one hour and will be tape recorded. The potential for an increase in emergency presentations and diagnostic tests, may mean that there are additional NHS costs of no treatment, in spite of the cost savings in medication. Therefore, the researchers will undertake an economic evaluation to assess the cost-effectiveness of no treatment versus full dose anticoagulation in patients with isolated SSPE. Nested CTPA study: 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. Estimated total trial duration is 54 months comprising of setup (6 months), recruitment (32 months), follow-up (12 months) and analysis/write up (4 months). Patients will be approached by a member of the local research team who will introduce the trial to them and provide the patient information sheet for their consideration. Patients will then be asked to sign an informed consent form to consent to the screening procedures and for their CTPA imaging to be transferred for central radiology review. Screening: Patients who also have DVT as well as a SSPE cannot take part in the trial. If they have already had a computed tomography (CT) scan or magnetic resonance imaging (MRI) to confirm DVT status they will need to have a ultrasound scan of their legs to look for DVT. Pregnant patients cannot participate in the trial therefore women likely to become pregnant will be required to take a pregnancy test. As part of the eligibility assessment patients will be required to have a physical examination, they will have their medical history, vital signs and current medication assessed. Patients will be asked to complete the EQ-5D-5L health questionnaire at baseline. If following screening the patient is found to be eligible they will be asked if they are willing to be randomised and sign an additional informed consent form. The patient will be randomized 1:1 to either anti-coagulation treatment for at least three months or no anti-coagulation treatment. Follow up: Primary outcome analysis at 3 months with patient follow up assessments via telephone at 30 days, 3 and 6 months post randomization. At the 4 week assessment patients will be contacted to provide data on recurrent VTE. At the 3 and 6 months assessment patients will be contacted and asked to complete the EQ-5D-5L health questionnaire. They will also be asked about symptoms relating to VTE, bleeding events, hospitalisations and bed days for VTE or bleeding, VTE recurrence, EQ-5D-5L, unscheduled visits to primary/secondary care for symptoms potentially related to VTE, whether anti-coagulation treatment has been stopped or started. The researchers will use an efficient design for 12 month follow-up through targeted extractions from NHS Digital and consent to access medical records. These extractions will include VTE recurrence at 12 months, rate of new diagnosis of pulmonary hypertension or right ventricular dysfunction (coded in hospital or HES record), death due to PE/VTE. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | - |
| Primary outcome measure | Recurrent venous thromboembolism (VTE), death-related VTE, or clinically relevant bleeding, assessed using case report forms at the 12 and 24 week follow up timepoints |
| Secondary outcome measures | 1. Reduction in recurrent VTE and bleedings event assessed using case report forms at the 12, 24 and 52-week timepoints 2. Reclassification rate of SSPE diagnoses made by acute reporting radiologists when reviewed by thoracic radiologists, recorded on a case report form at registration/randomisation 3. Healthcare resource use: hospitalisations, bed days, unscheduled primary and secondary care visits for recurrent VTE, clinically relevant bleeding or potentially related symptoms, measured using case report forms at the 12, 24 and 52-week timepoints 4. Healthcare costs assessed using case report forms at the 12, 24 and 52-week timepoints 5. Health-related quality of life measured using the EQ-5D-5L questionnaire at baseline, 12 and 24 weeks 6. Cost-utility (cost per QALY) measured using a case report form at 24 weeks and cost-effectiveness (cost per VTE avoided) measured at 52 weeks 5. Acceptability to patients and clinicians and health-seeking behaviours and health utilisation of a no anticoagulation treatment strategy for isolated SSPE, assessed through audio-recorded interviews which can occur at any point throughout the trial |
| Overall study start date | 01/10/2019 |
| Overall study end date | 31/03/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 1466; UK Sample Size: 1466 |
| Participant inclusion criteria | 1. Age ≥18 years 2. SSPE diagnosed by the radiologist at the trial site by CTPA or CT thorax with IV contrast 3. No evidence of proximal deep vein thrombosis on doppler ultrasonography or CT/MR venography 4. Heart rate <110 bpm 5. Systolic blood pressure ≥100 mmHg 6. Oxygen saturation ≥90% 7. Written signed informed consent to the trial |
| Participant exclusion criteria | 1. Indication for hospital admission 2. >7 days empirical anticoagulation treatment immediately prior to randomisation 3. <28 days since first symptoms of proven or clinically suspected COVID-19 4. Known stage 5 chronic kidney disease 5. 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 6. Patients with previous unprovoked PE, thrombophilia or requiring long term anticoagulation for another reason 7. Patients with a DVT / thrombus of an unusual site (e.g. upper limbs, associated with a line) that requires anticoagulation 8. Patients with active bleeding 9. 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 10. Pregnancy confirmed by positive pregnancy test or post-partum period or actively trying to conceive 11. Inability to comply with the trial schedule and follow-up 12. Participation in a CTIMP study |
| Recruitment start date | 08/04/2021 |
| Recruitment end date | 30/06/2023 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Skipton Road
Steeton
BD20 6TD
United Kingdom
Acre Street
Lindley
Huddersfield
HD3 3EA
United Kingdom
Maes-Y-Coed Road
Cardiff
CF14 4HH
United Kingdom
369 Fulham Road
London
SW10 9NH
United Kingdom
Withington
Manchester
M20 4BX
United Kingdom
Stirling
FK8 1DX
United Kingdom
Frimley
Camberley
GU16 7UJ
United Kingdom
Wolverhampton Road
Heath Town
Wolverhampton
WV10 0QP
United Kingdom
2-4 Waterloo Place
Edinburgh
EH1 3EG
United Kingdom
Southmead Road
Westbury-On-Trym
Bristol
BS10 5N
United Kingdom
Holdforth Road
Hartlepool
TS24 9AH
United Kingdom
Rake Lane
North Shields
NE29 8NH
United Kingdom
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
Gartnavel Royal Hospital
1055 Great Western Road
Glasgow
G12 0XH
United Kingdom
London Road
Reading
RG1 5AN
United Kingdom
Castle Lane East
Bournemouth
BH7 7DW
United Kingdom
North Manchester General Hospital
Delaunays Road
Crumpsall
Manchester
M8 5RB
United Kingdom
Bath
BA1 3 NG
United Kingdom
Stott Lane
Salford
M6 8HD
United Kingdom
Dudley Road
Birmingham
B18 7QH
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
Poplar Grove
Stockport
SK2 7JE
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Stoke-On-Trent
ST4 6QG
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Magdala Avenue
London
N19 5NF
United Kingdom
Charles Hastings Way
Worcester
WR5 1DD
United Kingdom
Oxford Road
Manchester
M13 9WL
United Kingdom
Wigginton Road
York
YO31 8HE
United Kingdom
Burton Road
Kendal
LA9 7RG
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Hollyhurst Road
Darlington
DL3 6HX
United Kingdom
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Herries Road
Sheffield
S5 7AU
United Kingdom
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom
Sponsor information
University/education
c/o Dr Birgit Whitman
Room 117, Aston Web Building
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)1214158011 |
|---|---|
| researchgovernance@contacts.bham.ac.uk | |
| Website | http://www.birmingham.ac.uk/index.aspx |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 31/05/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. The study protocol and patient trial documents are available on the trial website: https://www.birmingham.ac.uk/stop-ape 2. Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Other publications | Process evaluation | 26/02/2025 | 28/02/2025 | Yes | No |
Editorial Notes
28/02/2025: Publication reference added.
04/10/2022: The study was stopped due to poor recruitment.
08/04/2021: The following changes were made to the trial record:
1. The recruitment start date was changed from 25/01/2021 to 08/04/2021.
2. ClinicalTrials.gov number added.
09/12/2020: The recruitment start date was changed from 01/12/2020 to 25/01/2021.
09/11/2020: The recruitment start date has been changed from 01/11/2020 to 01/12/2020.
24/09/2020: Trial's existence confirmed by the NIHR.
