Not a shift goes by in which a provider does not consider a pulmonary embolism (PE) as a possible diagnosis. No matter if you love or hate the D-dimer, it has become entrenched in the medical evaluation for PE! Unfortunately, at times providers are becoming reliant solely on a D-dimer test, when evaluating patients with the potential of a pulmonary embolism… Yet, I believe when used in the appropriately risk stratified patient, a D-dimer can avoid further potentially harmful workups, radiation, and contrast exposure.
The pulmonary embolism rule-out criteria (PERC) was created to reduce testing in patients who have a very low probability of PE (i.e. prevalence of <1.8%) in which further testing would not be necessary. The PROPER Trial was a prospective randomized clinical trial that took very low-risk patients with suspected PE, randomizing patients to a PERC strategy versus conventional strategy, which did not result in an inferior rate of thromboembolic events for over 3 months.  These findings support the safety of PERC for very low-risk patients!
Conventional high-sensitivity D-dimer testing (<0.5ug/mL) is the backbone of the modern PE workup. It has been extensively studied and carries an overall sensitivity of 99.5% when applied to patients with low pretest probability of PE.  The corresponding specificity of 41%, however, leaves much to be desired. The overall low specificity using a conventional D-dimer cutoff has led to a significant burden of over testing with advanced imaging.
As you review this article it is important to know what type of d-dimer assay you have at your respective institutions and make sure that it correlates to the studies mentioned within this article. Broadly, d-dimer testing can be described as quantitative tests (i.e. results expressed as a number), semi-quantitative, or qualitative (i.e. results expressed as positive or negative). The ADJUST PE trial used D-dimer results from the following six different quantitative high-sensitivity D-dimer assays:
- D-Dimer Exclusion test (bioMérieux)
- Second-generation Tina-quant
- Cobas h 232 (Roche)
- STA-Liatest D-Dimer **Used at both Mercy Main & MWL but not at our Urgent Cares**
- D-Dimer HS 500 (IL Diagnostics)
- Innovance D-Dimer (Siemens)
Age Adjusted D-Dimer
A D-dimer naturally increases based on age as well as with many comorbid diseases [1-3, 24] This elevation with age results in a higher proportion of older patients with D-dimer concentrations greater than the conventional cut-off for VTE.[4-6] This can potentially lead to more imaging, which usually is low yield. Specificity can range from 49 – 67% in patients ≤ 50 years of age, but in older patients (i.e. ≥ 80 years of age) the specificity is quoted as 0 – 18%. The result of this is, older patients often have more diagnostic imaging.
Based on the 2018 American College of Emergency Physicians (ACEP) Clinical Policy on venous thromboembolism (VTE), ACEP provided a Level B recommendation that “In patients older than 50 years deemed to be low or intermediate risk for acute PE, clinicians may use a negative age-adjusted D-dimer result to exclude the diagnosis of PE.”
The new ACEP Clinical Policy states that using an elevated cutoff compared to conventional levels can reduce harmful workups, radiation and contrast exposure, costs of further evaluation, and ED length of stay, while potentially improving patient satisfaction. The American College of Physicians states “Clinicians should use age-adjusted D-dimer thresholds (age × 10 ng/mL rather than a generic 500 ng/mL) in patients older than 50 years to determine if further imaging is warranted.”
Multiple studies have evaluated using an age-adjusted D-dimer and its reliability in the evaluation of PE and DVT, with Douma et al. performing a derivation of age-adjusted D-dimer in conjunction with clinical probability, followed by multiple validations for PE and DVT (Penaloza et al. 2012, van Es et al. 2011, Schouten et al. 2012, Renée A Douma et al. 2012).[8-14]
Is Age Adjusted D-dimer safe?
Yes, with similar sensitivities for PE and similar miss rates (approximately 1%). One of the larger prospective, multi-centered studies included over 3,000 ED patients, with an overall prevalence of PE reaching 19%. Patients were risk stratified first, with 87% deemed non-high risk (by revised Geneva or 2-level Wells’ score). At three months, there was a total of 1 missed PE in 331 patients (0.3%) using a D-dimer level above 500 mcg/L but below the age-adjusted cutoff, with 1 missed PE in patients with a D-dimer level below 500 as well (for a grand total of 2 patients).
A meta-analysis combining this study with five others (7,268 patients) with 22% prevalence of PE. Age-adjusted levels in combination with PE unlikely stratification had a miss rate of 0.9%, with one fatal PE, compared to the conventional cutoff miss rate of 0.7%. The previously mentioned derivation studies demonstrate low miss rates (ranging from 0.2% to 2.5% for age-adjusted levels) and high sensitivities for excluding VTE.[9-12,16-19]
If this information was not compelling enough, Dr. Eric Asbe conducted a 3 year retrospective Cost-Benefit analysis on the Age-Adjusted D-dimer at Mercy Medical Center. Only one missed case was identified and no deaths were identified in his study.
Is it clinically useful?
Age-adjusted D-dimer can reduce further workup, with higher rates of PE exclusion. The Righini et al. study found using an age-adjusted level increased the proportion of patients with negative D-dimer results, from 28% to 40%. The Van Es et al. study found an increase in 5% while Flores et al. found a 9% increase in exclusion rates.[14,16] Other studies have found similar rates in decreased need for further workup, varying from 4% to 9%.[8,10,12,17-19]
How do you perform age adjusted D-dimer testing?
- The formula is: Age (years) x 10 ug/mL for patients > 50 years of age
- Example: Patient age 78 = age adjusted D-dimer of 0.780 ug/mL
What about tests using a cutoff other than 500 mcg/L? At Mercy Medical Center Des Moines we use 0.5 mcg/ml, although this may appearing confusing, we only need to modify the 1000th spot to make the adjustment as demonstrated above (in the example).
In the comments of our D-dimer test, Dr. Mathew Andres Chief of Pathology at Mercy Medical Center – Des Moines has added the following:
- (Medium Importance) Interpretive Data by Summers, Jake, Med Technologist on October 31, 2018 18:32 US/Central Use of the STA-Liatest D-dimer (Stago) with a cut off value of 0.5 mcg/ml (FEU) provides a negative predictive value for exclusion of thrombosis of 95-100%. Recent evidence suggests using clinical pretest probability and age-adjusted cutoffs to improve the performance of D-dimer testing in patients greater than 50 years of age. An internal study involving 4348 patients, concluded that using the Wells score and age-adjusted D-dimer significantly reduced the false positive rate when compared to the standard D-dimer reference range.
Adjusting the D-dimer based on patient age can increase the number of patients with a negative D-dimer result, reducing further imaging in patients, while not significantly increasing the risk of missed PE. However, only apply D-dimer to patients with low pretest probability using a validated prediction tool (Wells’, Geneva, etc.). If the patient meets this criterion, then move forward by taking the patient’s age X 10 mcg/L for FEU. If the D-dimer is below this threshold, you have risk stratified the patient to a level where further evaluation is associated with greater harm than benefit.
In patients > 50 years of age, using a clinical probability assessment plus an age adjusted D-dimer cutoff increases the number of patients that can be safely ruled out for PE/DVT. It is important to note that different hospitals will use different assays of d-dimer and so the age adjusted cutoff used in the above studies may not be applicable to your institution.
Instituting a change of practice is challenging. It will require modification of years of routine clinical practice for some. It may be uncomfortable and resisted by some, but providers should embrace the new evidence and update their practice.
Clinical gestalt is superior to risk stratification and utilization of the above process is only encouraged when the diagnosis is elusive
If you have time listen to the PODCAST conducted with Dr. Tim McCoy & Dr. Eric Asbe
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- Lippi G,Bonfanti L, Saccenti C, Cervellin G. Causes of elevated D-dimer in patients admitted to a large urban emergency department. Eur J Intern Med.2014 Jan;25(1):45-8.
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- Jaconelli T, Eragat M, Crane S. Can an age-adjusted D-dimer level be adopted in managing venous thromboembolism in the emergency department? A retrospective cohort study. Eur J Emerg Med.2017 Jan 10. doi: 10.1097/MEJ.0000000000000448. [Epub ahead of print]
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- Raja AS, Greenberg JO, Qaseem A, et al; Clinical Guidelines Committee of the American College of Physicians. Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015;163:701-711.
- Douma RA, le Gal G, Söhne MD, et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. 2010;340:c1475.
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- van Es J, Mos I, Douma R, et al. The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded. Thromb Haemost. 2012;107:167-171.
- Schouten HJ, Koek HL (Dineke), Oudega R, et al. Validation of two age dependent D-dimer cut-off values for exclusion of deep vein thrombosis in suspected elderly patients in primary care: retrospective, cross sectional, diagnostic analysis. The BMJ. 2012;344:e2985. doi:10.1136/bmj.e2985.
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- Schouten HJ, Geersing GJ, Koek HL, et al. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis.The BMJ. 2013;346:f2492.
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- Freund Y, Cachanado M, Aubry A, Orsini C, Raynal P, Féral-Pierssens A, Charpentier S, Dumas F, Baarir N, Truchot J, Desmettre T, Tazarourte K, Beaune S, Leleu A, Khellaf M, Wargon M, Bloom B, Rousseau A, Simon T, Riou B, Effect of the Pulmonary Embolism Rule-Out Criteria on Subsequent Thromboembolic Events Among Low-Risk Emergency Department PatientsThe PROPER Randomized Clinical Trial. 2018;319(6):559–566. doi:10.1001/jama.2017.21904
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