D-Dimer in High-Risk PE: A Gamble Worth Taking?

\Background: The current standard care for evaluating pulmonary embolism (PE) advises against D-dimer testing in patients with a high clinical probability. European and American guidelines emphasize a sequential diagnostic approach based on pretest probability assessment using either a formal clinical decision instrument (e.g., Wells’, Revised Geneva) or clinical gestalt. D-dimer testing is commonly used to rule out PE in low- and moderate-risk patients due to its high sensitivity and negative predictive value. A negative D-dimer is believed to be inadequate to exclude PE in high-risk patients, and since the test doesn’t change probability, it should be avoided. Instead, guidelines advocate for direct chest imaging, such as CT pulmonary angiography, to confirm or exclude PE in this population. However, there is minimal data on the utility of D-dimer testing in high-risk patients.

Article: Bannelier H et al. Failure rate of D-dimer testing in patients with high clinical probability of pulmonary embolism: Ancillary analysis of three European studies. Acad Emerg Med 2024. PMID: 39487597

Clinical Question: Can a negative D-dimer safely exclude PE in patients with high pre-test probability for PE (as determined by Wells or Revised Geneva Scores)?

Population: Patients with a high clinical probability of PE and a D-dimer measurement in the ED. 

Outcomes:

• Primary: Rate of missed PE in high-risk patients with a negative D-dimer at index visit or 3-month follow-up
• Secondary: Rate of missed PE in high-risk patients using a 500 ng/mL D-dimer threshold at index visit or 3-month follow-up

Design: Post hoc analysis of three European studies: PROPER, MODIGLIANI, and TRYSPEED.

Exclusions:

• Missing D-dimer value
• No Revised Geneva score or Wells’ score available
• No assessment of PE by CTPA or 3-month follow-up
• Inconclusive CTPA

Results:

Primary results

• 651 patients were included for analysis. 
  • 70 of these patients were below the age-adjusted D-dimer threshold. 
  • 48 were below the 500 ng/ml threshold. No PEs were missed.  

Critical Results: 

Strengths:

• Researchers asked a clinically relevant question that had not previously been researched.
• Despite this being a secondary analysis, the primary studies from which the data is drawn are methodologically strong.

Limitations:

• Post-hoc analyses may introduce biases as the data from these European studies were not initially collected for this purpose. 
• Study heterogeneity:
  • The studies PROPER and MODIGLIANI were designed to evaluate patients with a low probability of PE as assessed by clinical gestalt. However, objective scores were assigned in this study based on Wells’ and revised Geneva, which may categorize patients at higher risk than clinical gestalt. 
  • The TRYSPEED study’s reliance on retrospective CTPA data without 3-month follow-up, combined with the exclusion of inconclusive results and a focus on D-dimer comparisons to CTPA rather than clinical follow-up, may underestimate the strategy’s failure rate. 
  • The 3 studies had different exclusion criteria and different methods of patient selection. We do not know why certain patients in these studies underwent D-dimer testing, which biases the sample.
  • The significant difference in negative D-dimer rates between the TRYSPEED study and the other cohorts likely arises from TRYSPEED, including only patients who underwent CTPA. In contrast, the PROPER and MODIGLIANI cohorts include all suspected PE patients regardless of whether they had CT imaging.
• Results might not be generalizable to populations with differing baseline risks or healthcare practices outside of Europe.
• Because of the small number of patients, the confidence intervals for the primary outcome are wide, which precludes a definitive conclusion.

Discussion:

• The “high-risk” group may not have been high-risk as evidenced by the relatively low rate of diagnosed PE in this group (~ 30%). Historically, high-risk groups have ~ 60% PE rate.
• A negative D-dimer (age-adjusted or fixed threshold) appears to reliably exclude PE in this patient population, even in high-risk individuals. 
  • However, the inherent biases in this type of study introduce several uncertainties, and the wide confidence intervals further weaken the validity of this approach. 
  • The primary utility of a D-dimer lies in its ability to rule out PE when negative, allowing clinicians to avoid CT imaging. 
  • Yet, in this study, the vast majority of high-risk patients had a positive D-dimer. 
  • In clinical practice, this suggests that ordering a D-dimer in high-risk patients is more likely to delay definitive imaging than it is to allow you to forgo imaging altogether. 
• This approach could be considered in specific scenarios where a negative D-dimer is obtained, and the patient is later recognized as high-risk. In such cases, the reliability of a negative D-dimer might still justify withholding imaging. 

Author Conclusion: “In this study, ruling out pulmonary embolism in high-risk patients based on D-dimer below the age-adjusted threshold was safe, with no missed pulmonary embolism. However, the sample size was not large enough to draw a definitive conclusion on the safety of this strategy.”

Clinical Take Home Point: It may be reasonable to consider forgoing CTPA imaging in high-risk PE patients if they have a negative D-dimer, but more research that is prospective with larger cohorts is needed to determine the safety of this approach

For More Thoughts on This Topic Checkout:

Age-Adjusted D-dimer:

• Core EM: Age Adjusted D-dimer in PE – The ADJUST-PE Trial
• REBEL EM: PEGeD Study – Is It Safe to Adjust the D-Dimer Threshold for Clinical Probability?
• REBEL EM: Age Adjusted D-dimer Testing
• The Bottom Line: PEG-eD
• St. Emlyn’s: Level Pegging? JC and the PEGeD Study
• JournalFeed: Is it Time to Adjust D-Dimer Thresholds to Our Clinical Pretest Probability?
• The SGEM: SGEM #282 – It’s All ‘Bout That Bayes, ‘Bout That Bayes – No Trouble – In Diagnosing Pulmonary Embolism

YEARS Criteria

• REBEL EM: The YEARS Study – Simplified Diagnostic Approach to PE
• EM Lit of Note: YEARS, But Wells

ACEP Clinical Policy:

• REBEL EM: ACEP Clinical Policy on Acute VTE 201
• FOAMCast: Pulmonary Embolism Risk Stratification and ACEP Clinical Policy

Peer Review: Anand Swaminathan MD, MPH