Stopping anticoagulation for isolated or incidental pulmonary embolism: the STOPAPE RCT protocol

Research Question: Is withholding anticoagulation for patients with isolated or incidental sub-segmental pulmonary embolism (ISSPE) clinically and cost effective compared with full anticoagulation for three months?

Background: There has been an increase in the diagnosis of subsegmental pulmonary embolism (SSPE) since the advent of computed tomography pulmonary angiography (CTPA) to investigate patients with suspected pulmonary embolism (PE). SSPE is not often detectable with older nuclear medicine based diagnostic imaging for ventilation/perfusion (V/Q) mismatch. The case fatality of PE has reduced as SSPE diagnoses from CTPA have increased. There is growing equipoise about the optimal treatment for patients with SSPE, given that full anticoagulation has significant risks of bleeding and SSPE was not often diagnosed previously with V/Q scanning and therefore most likely left predominantly untreated prior to the introduction of CTPA scanning.

Objectives:
1. Determine whether withholding anticoagulation for isolated or incidental SSPE (i.e. SSPE with no co-existing deep vein thrombosis) reduces the harms of recurrent thromboembolism and major bleeding compared with three months of full anticoagulation at 3, 6 and 12 months
2. Determine the rate of complications of anticoagulation therapy (predominantly bleeding) in patients with ISSPE.
3. Determine whether not treating ISSPE is acceptable to clinicians and patients.
4. Determine the reclassification rate of ISSPE diagnoses made by general reporting radiologists when reviewed by specialist respiratory radiologists and develop a set of rules to improve general radiologists' diagnoses of SSPE.
5. Assess cost-effectiveness of not treating patients with ISSPE with anticoagulation, taking a health service perspective.

Methods: Prospective individually randomised open controlled trial with blinded end point committee assessment for outcomes, powered for non-inferiority for recurrent venous thromboembolism (VTE) and for superiority for bleeding events. An internal pilot phase is included for feasibility and acceptability of no anticoagulation. We planned to recruit 1466 patients from at least 50 acute hospital sites. Allowing for a drop out rate of 15%, this would have given us 90% power to detect a reduction in major and clinically relevant non-major bleeding from 7.3% in the anticoagulation arm to 3% in the intervention arm. We were powered to determine that a strategy of no anticoagulation was non-inferior to anticoagulation with an upper margin of a 2.3% increase in recurrent VTE from an expected rate of 2% in those who receive full anticoagulation.

We also planned to undertake a study comparing acute reporting radiologists’ diagnoses of SSPE from all CTPAs with specialist respiratory radiologists. This would have allowed us to determine safety in the pilot study (i.e. patients with PE that was in fact larger than sub segmental would have been identified) and develop guidance for SSPE diagnosis for general radiologists. Patients with lived experience of thrombosis contributed to all aspects of the trial design and were part of trial management group.

Progress of Study:
The STOPAPE trial was stopped prematurely due to a low recruitment rate in the wake of the COVID pandemic and prioritisation of recovery of the NIHR research portfolio. There are no outcome data available for this trial. Separate NIHR Library publications will detail the linked qualitative study examining the views of patients and clinicians around withholding anticoagulation for ISSPE as well as presenting all collected data of recruited patients.

This project was funded by the National Institute for Health and Care Research (NIHR) HTA programme (NIHR 128073) and will be published in XXX Journal: Vol. XX, No. XX.

Trial Registration: ISRCTN15645679