A D-Dimer for Patients with High Pre-Test Probability of PE?
/Clinical question
Can a negative D-dimer effectively rule out pulmonary embolism (PE) for patients considered to be high risk for PE?
Background
Pulmonary embolism is a life-threatening cardiovascular emergency that requires prompt recognition to initiate treatment. The diagnosis can be easily missed due to non-specific clinical presentations, which has led to the development of several risk algorithms to identify the likelihood of PE, which are reviewed here. The current standard of care is to risk stratify low to moderate risk patients with a D-dimer whereas high risk patients proceed to CT with pulmonary angiography (CTPA).
Whether a D-dimer can be used to effectively rule-out PE in those with high pretest probability has not been directly studied. The D-dimer has excellent negative predictive value, but it is more likely to be positive for those with high pretest probability for PE. This ultimately leads to CTPA, which could have been expedited by recognizing the patient as high risk and immediately undergoing imaging. Proceeding directly to CTPA is not without its own risks though, given concern for overdiagnosis of subsegmental PEs, unnecessary exposure to radiation, and false positive results.
Study design
This was a retrospective post-hoc analysis of databases from three large European studies. Each of these studies investigated diagnosis of pulmonary embolism and included patient Wells or revised Geneva scores. Each study attempted to answer different clinical questions and had different study designs. Links to the trials and brief details of each are included below.
To be included in the study analysis, the patient had to have (1) a high clinical probability of PE as defined by Wells >6 or revised Geneva >10 and (2) a D-dimer. Patients were excluded if they were missing a D-dimer, missing a Wells or revised Geneva score, or were not assessed for PE by either CTPA or 3-month follow-up.
The primary outcomes of this study were to determine the failure rate of age-adjusted D-dimer (less than 500 ng/mL in patients younger than 50, age multiplied by 10 ng/mL in patients older than 50) and the failure rate of a fixed D-dimer (less than 500 ng/mL)
Using Bayesian statistics, the authors determined the posterior probability that the failure rate of the strategy is below 2%, which is the acceptable diagnostic failure rate for PE suggested by the International Society on Thrombosis and Haemostasis.
Results
Of over 12,300 patients among the three studies, 651 met inclusion and exclusion criteria. 584 of these were from TRYSPEED, whereas 67 were from PROPER and MODIGLIANI.
Of these 651 patients:
70 had D-dimers below age-adjusted threshold
48 had D-dimers below fixed threshold
Of these patients with negative D-dimers (both age-adjusted and fixed), none had PEs.
Strength and Pitfalls
This study asks a provocative question that challenges standard of care. It produced a compelling result suggesting that if patients classified as high risk for PE by Wells or revised Geneva scores had a negative D-dimer, they would be unlikely to have PE.
The biggest strength of this study is that it draws from three large European cohorts whose study designs were methodologically strong. The use of objective scoring systems such as Wells and revised Geneva minimizes clinical bias. That said, this study makes several critical errors that would preclude recommendations to change current practice patterns.
The first major concern is the data from each of these European studies was not initially collected to investigate high risk PE patients. In fact, PROPER and MODIGLIANI were designed specifically to investigate patients who were low to moderate risk for PE by clinical gestalt. The population used in this study’s analysis does not accurately represent the true population of high-risk patients.
Second, the analysis resulted in dramatic data asymmetry, with over 90% of data coming from TRYSPEED alone. This leads to a significant data skew that over represents TRYSPEED, which does have several weaknesses compared to PROPER and MODIGLIANI. First, D-dimers in TRYSPEED were nearly triple that of the PROPER and MODIGLIANI trials, likely due to TRYSPEED including only patients who had undergone CTPA in their dataset. TRYSPEED had no 3-month follow-up and excluded inconclusive results, which would underestimate the failure rate. Additionally, only 7.6% of the patients in TRYSPEED included in the analysis were in the high pretest probability category, suggesting it was an inappropriate study population to draw data from.
Finally, the results leave room for doubt. Despite the calculated failure rate of 0%, the upper limits of the 95% confidence intervals extend to 6.5% and 7.4%. Although Bayesian analysis estimates a 76% probability that the failure rate is below 2%, there is still a significant chance that this strategy is above an appropriate diagnostic miss rate.
Clinical Takeaways
From this study alone, we cannot recommend the use of D-dimer testing in patients with high pretest probability for PE. Current practice should remain the same, and these patients should proceed directly to CTPA.
That said, this study’s results would justify the development of a prospective trial to investigate the role, safety, and optimal threshold of D-dimer testing in high-risk PE patients.
Additionally, the study suggests D-dimer testing could be used in specific clinical scenarios involving high-risk PE patients. If a CTPA cannot be performed, if a CTPA is indeterminant due to poor opacification or artifact, or if withholding anticoagulation would be desirable, a negative D-dimer could be considered in medical decision making when deferring treatment
Authorship
Written by Daniel Artiga, PGY-3, University of Cincinnati Department of Emergency Medicine
Audio Editing by Anita Goel, MD, Adjunct Assistant Professor, University of Cincinnati Department of Emergency Medicine
Editing and Posting by Jeffery Hill, MD MEd, Associate Professor, University of Cincinnati Department of Emergency Medicine
Cite As: Artiga, D., Hill, J., Goel, A. A D-Dimer for Patients with High Pre-Test Probability of PE? TamingtheSRU. www.tamingthesru.com/blog/journal-club/a-d-dimer-for-patients-with-high-pre-test-probability-of-pe. 4/30/2025.
