With Age, Comes Wisdom and Maybe a new D-dimer Cutoff?

Get with the guidelines and avoid over-scanning.

Case 1: A 72-year-old female presents with mild shortness of breath for several days. She has a history of hypertension and hyperlipidemia. She was tachycardic initially, which has resolved. The rest of her exam is normal, with clear lungs and normal lower extremities. Her ECG is unactionable, and her chest X-ray is also normal. She’s low risk based on Wells’ Criteria, but could this be a PE? Is there something you can order to lower this risk even further? Please tell me it’s not a D-dimer…

No matter whether you love or hate the D-dimer, it’s here to stay and is used daily. Granted, we order too many inappropriate D-dimer tests when evaluating patients with potential pulmonary embolism (PE) or deep venous thrombosis (DVT), but when used in the appropriately risk stratified patient, D-dimer can avoid further potentially harmful workups, radiation and contrast exposure.

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Before we get started, let’s establish some ground rules. This article will address quantitative D-dimer assays, not qualitative assays, which suffer from poor test characteristics. We will not evaluate the controversial topic of whether D-dimer is appropriate at all in the evaluation of VTE — yes, there are many who state D-dimer is essentially worthless. We will also not delve into the over-workup of patients for PE (a completely other topic), or the likely overdiagnosis of PE on computed tomography (CT).

The Problem with D-dimer and Age

One major issue with D-dimer is that it naturally increases based on age, as well as with many comorbid diseases (smoking, post-operative state, malignancy, atrial fibrillation, sickle cell disease, superficial thrombophlebitis, autoimmune disorder, acute inflammatory states such as sepsis, trauma and many others).[^1-3] This elevation with age results in a higher proportion of older patients with D-dimer concentrations greater than the conventional cut-off for VTE — fibrinogen equivalent units (FEU) 500 mcg/L or D-dimer units (DDU) 250 mcg/L — and even less specificity with a D-dimer.[^4-6] This can potentially lead to more imaging, which is typically low yield. However, keep in mind the risk of PE increases with age.[^5,6] Not only do we have a baseline elevated D-dimer, but higher risk for PE as well. Is there a way to match a patient’s age with a different D-dimer cutoff and is it supported in the literature?

Based on the 2018 American College of Emergency Physicians (ACEP) Clinical Policy on venous thromboembolism (VTE), this may be ready for primetime, with ACEP providing 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.”[^6]

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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. This comes with the potential of missing PE or misapplying age-adjusted D-dimer due to confusion with units (FEU or DDU).[^6]

Are there other organizations that recommend using age-adjusted D-dimer? 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 whether imaging is warranted.”[^7]

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,[^8] 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).[^9-12] There are even meta-analyses evaluating this topic.[^13,14]  Literature supports using age-adjusted D-dimer in conjunction with risk stratification and we will look at several of the key studies evaluating this test. To do this, we are going to break this down based on ACEP’s three primary questions: 1) Is age-adjusted D-dimer safe? 2) Is it clinically useful (i.e. will it decrease further workup)? 3) How does age-adjusted D-dimer perform in geriatric subgroups?

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Is age-adjusted D-dimer safe?

Yes, with similar sensitivities for PE and similar miss rates (approximately 1%).[^5] One of the larger prospective, multi-centered studies included over 3,000 ED patients, with an overall prevalence of PE reaching 19% (higher than other U.S. studies).[^15]  Patients were risk stratified first, with 87% deemed non-high risk (by revised Geneva or 2-level Wells’ score). At three months, there were 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!).[^15]

A meta-analysis combining this study with five others (7,268 patients) with 22% prevalence of PE.[^14] 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%.[^14]  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 in U.S. and international populations,[^9-12,16-19] though several of these studies did not provide pretest probabilities.[^17-19]

Key Point: Age-adjusted D-dimer is safe, with similar miss rates, when compared to using conventional D-dimer levels in patients deemed non-high risk for PE/DVT.

Is it clinically useful (or in other words, will it decrease further workup)?

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%.[^15] The Van Es et al. study found an increase in 5%¹⁴ while Flores et al. found a 9% increase in exclusion rates.[¹⁶] Other studies have found similar rates in decreased need for further workup, varying from 4% to 9%.[^{8,10,12,17-19]}

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Key Point: Using age-adjusted levels can decrease further workup when used appropriately (in non-high risk patients by risk stratification).

How does age-adjusted D-dimer perform in geriatric subgroups?

We’ve looked at those over age 50 years, but what about those greater than 75 years? The Righini et al. study found the PE exclusion rate went from 6.4% to 29.7% using age-adjusted D-dimer for those > 75 years, with no missed PE’s.[^15]  Furthermore, 1 in 16 would have PE ruled out with a conventional cutoff, compared to 1 in 3.4 using an age-adjusted strategy.[^15] Van Es et al. found an increase from 8% to 20%, though the miss rate increased from 0% to 2.1% for missed PE.[^14] Other studies have found rates of PE exclusion increasing by 5% to 14%, with similar miss rates.[^16-19]

Key Point: Using age-adjusted levels in patients older than 75 years can exclude PE at higher rates, compared to conventional levels.

Bonus:

1. What about tests using a cutoff other than 500 mcg/L? Like we discussed, one FEU equals about half of one DDU.[^4-6] Thus 500 FEU equals 250 DDU. One study used an age-adjusted formula of age X 5 ng/mL for those older than 50 years and non-high risk for DVT and PE, which found no increase in missed PE and improved specificity (78% from 68%).[^4,6] A recent 2017 retrospective study conducted in low risk patients found a decrease in need for further workup by 9.8% (from 64.9% to 74.7%), though for patients older than 75 years, this went from 37.6% to 63.6% (26% difference).[^4] However, we need more literature on the use of DDU for age-adjustment.
2. What about using a fixed cutoff of 1000 mcg/L FEU? Several studies have evaluated a cutoff of 1,000 mcg/L FEU. Kline et al. found a sensitivity of 92% using this cutoff, compared to a sensitivity of 94% for the conventional level.[^20] This missed 10 PEs, though nine were subsegmental.[^20] A study by Sharp et al. found a miss rate of 0.3% in ED patients using 1,000 mcg/L, compared to 0.2% for an age-adjusted level and 0.1% for conventional level.[^17] Fritz et al. found a sensitivity of 96% for 1,000 mcg/L, compared to 98% for age-adjusted level and 100% for conventional levels.[^19] Though 1,000 mcg/L seems promising, similar to DDU cutoff levels, more data are required.

Commentary: There are several issues with studies evaluating age-adjusted levels. Prevalence of PE varied across studies, and studies most commonly used clinical follow-up as the study gold standard. Though most studies assessed D-dimer in non-high risk patients, several studies did not provide information on patient risk stratification.[^17-19]

It’s impossible to say if investigators missed small PEs (an entirely different topic, as most of these PEs are probably not clinically relevant).  Another major issue is whether emergency physicians will use age-adjusted D-dimer levels, or even conventional levels, to stop their workup of PE if used in combination with a non-high risk PE patient. We have seen in the past that D-dimer can actually increase workups when widespread utilization is encouraged. [^21] This strategy will miss PEs; there’s no way around it. While a miss rate of 1% may be acceptable to most, we fear that one miss that results in death. 

Back to our case…

You order a D-dimer for the patient, which returns at 556 mcg/L, below the age-adjusted cutoff of 720 (patient age X 10). You discuss the workup and laboratory results and the patient feels comfortable with no further evaluation for PE.

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 or intermediate pretest probability using a validated prediction tool (Wells’, Geneva, etc.). If the patient meets this criteria, then move forward by taking the patient’s age X 10 mcg/L for FEU or age X 5 mcg/L for DDU in patients older than 50 years. 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.

References:

1. Haase C, Joergensen M, Ellervik C, et al. Age- and sex-dependent reference intervals for D-dimer: evidence for a marked increase by age. Thromb Res. 2013;132:676-680.
2. 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.
3. Sadosty AT, Goyal DG, Boie ET, Chiu CK. Emergency department D-dimer testing. J Emerg Med.2001 Nov;21(4):423-9.
4. 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]
5. Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Thromb Haemost. 2000;83:657-660.
6. 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:e59-e109.
7. 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.
8. 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.
9. Penaloza A,Roy PM, Kline J, et al. Performance of age-adjusted D-dimer cut-off to rule out pulmonary embolism. J Thromb Haemost. 2012 Jul;10(7):1291-6.
10. 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.
11. 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.
12. Douma RA, Tan M, Schutgens REG, et al. Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. Haematologica. 2012;97(10):1507-1513.
13. 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.
14. van Es N, van der Hulle T, van Es J, et al. Wells rule and D-dimer testing to rule out pulmonary embolism. A systematic review and individual patient data meta-analysis. Ann Intern Med. 2016;165:253-261.
15. Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism. The ADJUST-PE study. JAMA. 2014;311:1117-1124.
16. Flores J, Garcia de Tena J, Galipienzo J, et al. Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis. Intern Emerg Med. 2016;11:69-75.
17. Sharp AL, Vinson DR, Alamshaw F, et al. An age-adjusted D-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications. Ann Emerg Med. 2016;67:249-257.
18. Gupta A, Raja AS, Ip IK, et al. Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism. Am J Emerg Med. 2014;32:1499-1502.
19. Friz HP, Pasciuti L, Meloni DF, et al. A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients. Thromb Res. 2014;133:380-383.
20. Kline JA, Hogg MM, Courtney DM, et al. D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography. J Thromb Haemost. 2012;10:572-581.
21. Goldstein NM et al. The Impact of the Introduction of a Rapid D-Dimer Assay on the Diagnostic Evaluation of Suspected Pulmonary Embolism. Arch Intern Med. 2001;161(4):567-571