Stopping anticoagulation for isolated or incidental sub-segmental pulmonary embolism: the challenges and lessons from the STOP-APE RCT

Background: The increasing use of computed tomography pulmonary angiography (CTPA) to investigate patients with suspected pulmonary embolism (PE) has led to an increase in diagnosis of small subsegmental pulmonary embolism (SSPE), which is rarely detectable with nuclear medicine based imaging, the standard imaging modality prior to the development of CTPA. The case fatality of PE has fallen in line with the increase in SSPE diagnoses from CTPA suggesting that we may be over-diagnosing PE (i.e. we may be diagnosing mild forms of PE which may not need any treatment). Given that full anticoagulation has significant side effects of bleeding and SSPE was not commonly diagnosed previously with nuclear medicine imaging (and therefore left predominantly untreated prior to CTPA scanning), there is growing equipoise about the value of full anticoagulation for patients with SSPE.

Methods: We tried to undertake an open randomised trial with blinded end point adjudication that recruited patients diagnosed with SSPE without evidence of thrombus in the leg veins, termed ‘isolated sub segmental pulmonary embolism’ (ISSPE). We allocated patients with ISSPE to either continuing with at least three months of full dose anticoagulation (standard care) or to stopping anticoagulation completely, unless they had a temporary hospital admission where prophylactic (i.e. preventative doses) of anticoagulation are standard practice. In addition, we interviewed patients and clinicians about their views on stopping anticoagulation for ISSPE which would be a substantial change from current practice. We planned to assess the accuracy of ISSPE diagnoses from CTPAs.

Results: The trial was stopped prematurely due to low recruitment. This was due to a combination of insufficient trial sites, problems with identifying patients who were suitable to be recruited at the time of acute assessment in hospital, the impact of COVID-19 on research infrastructure and a lower prevalence than had been predicted based on published studies. Our interview study showed that the intervention (i.e. changing practice to stopping treatment) is feasible although there were concerns raised about safety, which a trial would be needed to address. We did not have sufficient trial participants to determine accuracy of initial ISSPE diagnoses.

Conclusion: Although we were not able to answer the question of whether it is clinically and cost-effective to stop anticoagulating patients with ISSPE, we developed a protocol which can be used by future trialists who can successfully attract funding to address this research question, which remains important and an ongoing uncertainty for clinicians and patients.

Future Work: Trialists attempting to answer this research question should plan for longer recruitment times and ensure there is sufficient resource for a large number of recruiting centres.

Limitations: There were insufficient recruits to progress from the pilot phase to the full STOPAPE trial.

Trial Funding: This project was funded by the National Institute for Health and Care Research (NIHR) XXX programme and will be published in XXX Journal: Vol. XX, No. XX. See the NIHR Journals Library website for further project information. 


Trial registration: The trial was prospectively registered as ISRCTN15645679
Ethical Approval: Wales REC 6, Reference:20/WA/0256, approved 30.9.2020