Background: The overall mortality and case-fatality rate for pulmonary embolism (PE) are decreasing. Yet reporting is increasing, suggesting we are overdiagnosing PE. Furthermore, management with anticoagulation is not entirely benign and places a potential risk of bleeding upon the patient. However, when the threat of disease outweighs the risk from any possible complication, the decision to anticoagulate is easy to conclude.

The management of subsegmental PE remains controversial and lacks supporting evidence to guide treatment. Some believe anticoagulation is unnecessary, and subsegmental PEs lyse automatically with little patient consequences. Yet others proclaim that patients with subsegmental PEs should receive anticoagulation due to the high risk of recurrence and morbidity. 

The American College of Chest Physicians clinical practice guideline recommends surveillance instead of anticoagulation in patients with subsegmental PE without DVT. However, the authors formulated the recommendation based on expert consensus and moderate-quality evidence (Kearon et al., 2016). On the other hand, the ACEP guidelines on venous thromboembolic (VTE) disease acknowledge the lack of evidence and recommend consideration of individual patient risk profiles and preferences when deciding to anticoagulate patients with subsegmental PE (Wolf et al., 2018). Without high-quality evidence, it is difficult to assess the pros and cons of anticoagulation in this patient population.  

Clinical Question: What is the risk of recurrent VTE in patients with subsegmental PE without DVT, who are not on anticoagulation?

Article: Le Gal G et al. Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation: A Multicenter Prospective Cohort Study. Ann Intern Med. 2022. PMID: 34807722

 What They Did:

• The SubSegmental Pulmonary Embolism Study (SSPE)
• Multicenter prospective management cohort study
• Enrolled a total of 292 patients from 18 centers in Canada, France, the Netherlands, and Switzerland. Patients were enrolled in the ED.
• Study conducted from 2011-2021 
• Eligible patients underwent bilateral leg ultrasonography at enrollment and again at 5-7 days. 
• Patients with DVT were excluded from primary analysis and anticoagulated (Distal DVTs were left up to the treating physicians whether to anticoagulate)
• After patients with DVT were excluded, only 266 enrolled patients were included in primary analysis.

• Inclusion criteria: Newly diagnosed isolated subsegmental PE
  • 1 or more intraluminal filling defects on CTA with no proximal involvement
• Exclusion criteria: 
  • Active cancer
  • History of venous thromboembolism
  • Requirement for O2 therapy (to maintain SpO2 >92%)
  • Other indications for long-term anticoagulation
  • Pregnancy
  • Anticoagulated before enrollment
  • Hospitalized at the time subsegmental PE was diagnosed 

Outcomes:

• Primary outcome: 
  • Recurrent VTE within 90 days. Defined as a new DVT found proximal to the trifurcation of the popliteal vein.
  • Pulmonary angiography demonstrating a new constant intraluminal filling defect or cutoff of a vessel
  • Ventilation-perfusion scanning with a high probability of pulmonary embolism
  • CT pulmonary angiography showing a new intraluminal filling defect in a subsegmental or larger pulmonary artery
  • Pulmonary embolism at autopsy
• Secondary outcome: 
  • Death due to PE
  • Major bleeding is defined as a drop of at least 2g/dl of hemoglobin, occurring at a critical site, or contributing to death. 
  • Minor bleeding is defined as any bleeding not meeting major criteria. 

Results:

• 292 patients enrolled
  • 18 (6.2%) had DVT: 6 proximal and 22 distal
  • 10 (3.4%) had DVT on repeat US after an initial negative evaluation
  • 20 of the patients were started on anticoagulation
  • 8 patients with distal DVTs did not receive anticoagulation and were included in the final analysis
  • 6 other patients started anticoagulation during follow-up for another reason i.e. atrial fibrillation

Primary Outcome:

Secondary Outcome:

Strengths: 

• First prospective cohort study investigating the deferring of anticoagulation in patients with subsegmental PE
• Adequately powered, multicenter study increases external validity
• The study enrolled ED patients, which increases the generalizability
• Enrolled patients consecutively, limiting selection bias
• Outcomes were patient-oriented

Limitations:

• While the study enrolled patients from multiple countries, most were from a single country, Canada.
• The study population is a heterogeneous group, as 64% of participants were white.
• Highly resource-intensive study design. 
  • Participants needed two separate negative leg ultrasounds before inclusion. 
• Difficult to apply study methodology in the real world as there is significant cost and time required to bring patients back for leg ultrasound. 
• Excludes hospitalized patients, which selects for a healthier population and leads to selection bias
• Unclear why the study population was only followed for 90 days
  • One benefit of cohort studies is the ability to follow patients for a long period.
• There is no comparator.
• Only symptomatic patients were assessed with CTA, introducing the potential for verification bias.
  • It is possible the authors missed asymptomatic VTE recurrence. 
• The study was stopped early for safety but still met 97% of planned enrollment. 
  • Studies stopped early are at risk of overestimating results. 
• Only 266 of the 292 patients were included in the analysis. It would have been reasonable to include DVT found on screening ultrasounds as formal exclusion criteria. 
• For patients who were investigated with VQ scans, investigators did not discuss how they addressed low and intermediate probability VQ scans.
• It does not address how the 6 patients who withdrew consent and 2 patients who were lost to follow-up were handled. 

Discussion:

• Cohort studies
  • Cohort studies allow you to look at multiple outcomes. However, they are limited to a single exposure and therefore aren’t as good at establishing causality as a randomized trial would be due to potential confounders. For example, it is possible, though unlikely, that another exposure is causing the recurrence of VTE, which the study is unable to control for since the patients were not randomized. 
• Inside the numbers: 
  • The investigators attempted to determine the relative risk of developing recurrent VTE in patients with subsegmental PE without a proximal DVT who have not been anticoagulated.
  • Among these patients, the cumulative incidence of recurrent VTE was 3.1% (95% CI 1.6% – 6.1%).
  • 9.6% of patients with subsegmental PE were found to have DVT in the series of screening ultrasounds. 
  • The investigators found a higher than expected level of recurrent VTE.
  • NO patients with recurrent VTE had a fatal PE.
  • The rate of major and minor bleeding was relatively small but only 26/292 patients analyzed for the secondary outcome were anticoagulated. We might assume a higher rate of bleeding in a larger comparative group on anticoagulation.
• Loss to Follow-up
  • Patients lost to follow-up, and those who withdrew consent were not included in the final analysis. Many papers will assume patients lost to follow-up met the primary outcome. While these 8 patients seem like a relatively small number, it is the same as the number of patients who met the primary outcome. If this were an RCT, one additional patient meeting the primary outcome may potentially have a huge impact on statistical significance and sway the results. Investigators should explicitly state how patients lost to follow-up are handled.
• No Comparator
  • Evaluates patients longitudinally who are managed with a single treatment strategy and lack a control group. We must be cautious when interpreting and applying the information gleaned from studies without a control group. It’s impossible to know what the outcomes of a comparative group of similar patients who were anticoagulated would have been.

Authors’ Conclusions: “Patients with isolated single or multiple subsegmental pulmonary embolism who do not have proximal deep venous thrombosis have higher-than-expected rates of recurrent venous thromboembolism. This has implications for management of these patients with anticoagulation in clinical practice.”

Our Conclusions: This paper adds valuable insight into the incidence of recurrent subsegmental PEs. However, the notable flaws in the study design limit its use and do not provide clarity on the necessity for anticoagulation in patients with subsegmental PEs. Still, the results are interesting, and we hope the data guide future RCTs. 

Clinical Bottom line: 

Recurrence of VTE in subsegmental PE may be more common than once originally thought, and the incidence is likely underreported in this study due to methodological flaws. However, subsegmental PE appears to be nonfatal based on this study.

References:

1. Le Gal G et al. Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation: A Multicenter Prospective Cohort Study. Ann Intern Med. 2022. PMID: 34807722
2. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report [published correction appears in Chest. 2016 Oct;150(4):988]. Chest. 2016;149(2):315-352. PMID: 26867832
3. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Thromboembolic Disease: Wolf SJ, Hahn SA, et al. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Suspected Acute Venous Thromboembolic Disease. Ann Emerg Med. 2018;71(5):e59-e109. PMID: 29681319

For More Thoughts on This Topic:

• First10EM: What to do About Subsegmental Pulmonary Embolism?

Guest Post By:

Fang Zhou Yu, MBChB
PGY-3, Emergency Medicine Resident
Nuvance Health, Poughkeepsie, New york
Email: fang_zhouyu@hotmail.com

Marco Propersi, DO FAAEM
Vice-Chair, Emergency Medicine
Vassar Brothers Hospital, Poughkeepsie, New York
Twitter: @marco_propersi

Post-Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)