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

• ClinicalTrials.gov Identifier: NCT04727437
• Recruitment Status: Recruiting
• First Posted: January 27, 2021
• Last Update Posted: September 29, 2021
• Sponsor: University of Birmingham
• Collaborators: Royal United Hospitals Bath NHS Foundation Trust; Cimar
• Information provided by (Responsible Party): University of Birmingham

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Subsegmental Pulmonary Embolism Nos	Other: No treatment; Drug: Warfarin; Drug: direct oral anticoagulants; Drug: Low molecular weight heparin	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1466 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: STOPping Anticoagulation for Isolated or Incidental Subsegmental Pulmonary Embolism
• Actual Study Start Date: April 8, 2021
• Estimated Primary Completion Date: July 2023
• Estimated Study Completion Date: May 2024

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. A composite score of the number of recurrent venous thromboembolism and/or clinically relevant bleeding [ Time Frame: 3 months ]
   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.

Secondary Outcome Measures :

1. The change in frequency and severity of harmful events [ Time Frame: 6 and 12 months ]
   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.
2. Number of new diagnosis of pulmonary hypertension of right ventricular dysfunction identified from Hospital Episode Statistics. [ Time Frame: 12 months ]
   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.
3. Reclassification rate from thoracic radiologist review [ Time Frame: 32 months ]
   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.
4. Measuring the rate of net clinical benefit [ Time Frame: 3 and 6 months ]
   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.
5. Measuring the rate of mortality [ Time Frame: 3, 6 and 12 months ]
   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).

Other Outcome Measures:

1. Healthcare resource use and cost [ Time Frame: 12 months ]
   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.
2. Behavioural analysis of the participants [ Time Frame: 32 months ]
   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.
3. Behavioural analysis of the healthcare professionals [ Time Frame: 32 months ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Pooja Gaddu; 01214159120; p.gaddu@bham.ac.uk

Locations

United Kingdom

Surrey & Sussex Healthcare NHS Trust; Recruiting

Redhill, United Kingdom, RH1 5RH

Contact: Sarah Davies 01737 768511 ext 2804 sarah.davies60@nhs.net

Principal Investigator: Jenny Bacon

Sponsors and Collaborators

University of Birmingham

Royal United Hospitals Bath NHS Foundation Trust

Cimar

More Information

• Responsible Party: University of Birmingham
• ClinicalTrials.gov Identifier: NCT04727437
• Other Study ID Numbers: Worktribe 799297; 280586 ( Other Identifier: IRAS ); ISRCTN15645679 ( Other Identifier: ISRCTN )
• First Posted: January 27, 2021
• Last Update Posted: September 29, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Pulmonary Embolism; Embolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Heparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Warfarin; Anticoagulants; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action