April 28, 2014

Age Adjusted D-Dimer Testing

D-dimer testing is sensitive for thrombus formation, and in patients who are not high risk, this test is used to rule-out venous thromboembolism. D-dimer has been shown to increase with age, which can cause a lower specificity (i.e. more false positive tests) in older patients.  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, but a higher cut-off may lead to increased false negative cases (i.e. missed VTE) and make this strategy less safe. So could age adjusted d-dimer testing increase specificity without affecting sensitivity?

It is important to know what type of d-dimer assay you have at your institution and make sure that it correlates to the studies below.  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). More specifically there are 5 major types of d-dimer assays:

  1. DVT and PEEnzyme-Linked Immuosorbent Assay (ELISA)
  2. Latex Agglutination Assay
  3. Whole Blood assay (Simplired)
  4. Turbidimetric Assay
  5. Immunofiltration Assay

A nice review of some of the newer d-dimer tests can be found by Schutgens RE et al from 2003. Realize for the purpose of this post, we are specifically discussing quantitative d-dimer tests.

How do you perform age adjusted d-dimer testing?

  • The formula is: Age (years) x 10 ug/L for patients > 50 years of age
  • Example: Patient age 88 = age adjusted d-dimer of 880 ug/L

Where was age adjusted d-dimer testing derived and validated?

  • PE Derivation: [1]
    • Conclusion: Age adjusted d-dimer combined with clinical probability, greatly increased the proportion of older patients in whom PE could be safely excluded
  • PE Validation: [2]
    • Conclusion: Age-adjusted cut-off increased clinical usefulness of D-dimer in older patients
  • PE Validation: [3]
    • Conclusion: Irrespective of which clinical decision rule is used, age-adjusted d-dimer increases the number of patients > 50 years in whom PE can be safely excluded.
  • DVT Validation: [4]
    • Conclusion: Combination of low clinical probability of DVT, use of age dependent d-dimer cut-off value for patients > 50 years, DVT can be safely excluded, compared with the conventional cut-off value of 500 μg/L
  • DVT Validation: [5]
    • Conclusion: Age-adjusted d-dimer in combination with clinical probability greatly increases the proportion of older patients in whom DVT can be safely excluded 

Summary of Studies:  Age adjusted d-dimer testing appears to increase specificity in patients age >50 years, without affecting sensitivity

There has also been a systematic review [6] that looked to review the diagnostic accuracy of d-dimer testing in older patients (> 50 years) with suspected venous thromboembolism comparing conventional d-dimer testing with age adjusted d-dimer testing.

What they did:

  • Systematic review and meta-analysis
  • 12, 497 patients with non-high clinical probability for venous thromboembolism included
  • Comparison of conventional d-dimer vs age adjusted d-dimer

Results:

Conclusion: Age adjusted d-dimer testing increases specificity without modifying sensitivity in patients > 50 years of age.

What is the newest study to evaluate age adjusted d-dimer testing? [7] 

ThromboembolismThe ADJUST-PE Study

What they did:

  • Multicenter, prospective validation of diagnostic yield of age-adjusted d-dimer cutoffs
  • 19 centers in Belgium, France, the Netherlands, and Switzerland
  • 3346 Consecutive patients presenting to ED with clinically suspected PE
  • Applied either a revised Geneva score or a 2-level Wells score for PE followed by a high-sensitivity D-Dimer in non-high risk patients

Outcomes:

  • Failure rate of diagnostic strategy (i.e. Thromboembolic events during 3 month follow up)

Results:

  • Prevalence of PE was 19% (Higher than North American studies)
  • 2898 patients had a low or unlikely clinical probability of PE
  • 3 month failure rate in patients with a d-dimer level < 500ug/L was 1/810 patients (0.1%)
  • 3 month failure rate in patients with a d-dimer level > 500 ug/L but below age-adjusted cutoff was 1/331 patients (0.3%)
  • 3 month failure rate in patients with a d-dimer level > age-adjusted cutoff was 7/1481 (0.5%)
  • In patients > 75 years with age-adjusted d-dimer level vs a 500 ug/L conventional cutoff, PE exclusion went from 6.4% to 29.7%, without additional false negatives…this is a 5-fold increase.
  • 1 in 16 would have PE ruled out with a conventional d-dimer cutoff, but 1 in 3.4 would have PE ruled out with age-adjusted d-dimer cutoffs, with no increase in missed VTE

Limitations:

  • 2 different pretest probability scores and 6 different d-dimer assays were used…cutoffs for different d-dimer assays vary from 200 – 500 ug/L
  • Not a randomized clinical control study, so there was no control group
  • 7 patients were deceased in the > 500 ug/L and < age adjusted cutoff d-dimer, but only one had an autopsy to confirm diagnosis, therefore hard to exclude PE as the cause of death
  • Prevalence of PE was higher than what is cited in most North American studies, but the same rate as European studies
  • Patient follow up was not with the gold standard CTPA

Conclusion: Compared to a fixed d-dimer cutoff of 500 ug/L, the combination of pretest probability assessment with age-adjusted D-dimer is associated with a larger number of patients in whom PE can be ruled out, without a decrease in missed PE

Take Home Message

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 the same as your institution.

References:

  1. Douma RA 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. BMJ 2010. PMID: 20354012
  2. Penaloza A et al. Performance of Age-Adjusted D-Dimer Cut-Off to Rule Out Pulmonary Embolism. J Thrombi Haemostasis 2012. PMID: 22568451
  3. van Es J 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 Haemostasis 2012. PMID: 22072293
  4. Schouten HJ 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. BMJ 2012. PMID: 22674922
  5. Douma RA et al. using Age-Dependent D-Dimer Cut-Off Value Increases the Number of Older Patients in Whom Deep Vein Trhombosis can be Safely Excluded. Haematologica 2012. PMID: 22511491
  6. Schouten HJ 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. BMJ 2013. PMID: 23645857
  7. Righini M et al. Age-Adjusted D-Dimer cutoff Levels to Rule out Pulmonary Embolism: The ADJUST-PE Study. JAMA 2014. PMID: 24643601

Other people have also written about age adjusted d-dimer cutoffs, and for their thoughts checkout:

 

Cite this article as: Salim Rezaie, "Age Adjusted D-Dimer Testing", REBEL EM blog, April 28, 2014. Available at: https://rebelem.com/age-adjusted-d-dimer-testing/.
The following two tabs change content below.

Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of R.E.B.E.L. EM
13 Comments
  • Per Staffan
    Posted at 16:47h, 29 April Reply

    Thanks a lot, great overview.

    We are currently in a discussion with the internists. We can´t officially age adjust cut off yet because it would cause confusion, but in clinical practice we basically age adjust already if there is a high threshold for giving I.v contrast.

    Best Regards,
    Per Staffan

    • Salim Rezaie
      Posted at 16:53h, 29 April Reply

      TY for reading, sorry to hear confusion between departments. Why not have an EM/IM grand rounds and talk about the evidence and let faculty discuss, not argue, the reasons why or why not to use age adjusted d-dimer. As I am an EM/IM trained physician and currently practicing in both specialities, this is an area of interest for me. Whenever we have disagreements at our institution we have a combined grand rounds lecture going through pros and cons and come up with an algorithm, or protocol, or clinical decision that both groups agree upon. IMHO…the evidence is there and we should be using this. Hope this helps.

      Salim

  • Age Adjusted D-dimer Cut Offs - Emergency Medicine Ireland
    Posted at 14:21h, 30 April Reply

    […] Age Adjusted D-Dimer Testing – R.E.B.E.L. EM – Emergency Medicine Blog says: April 28, 2014 at 10:04 am […]

  • REBELCast Episode 2 - R.E.B.E.L. EM - Emergency Medicine Blog
    Posted at 17:22h, 30 June Reply

    […] REBEL EM: Age-Adjusted D-Dimer Testing […]

  • ADJUST-PE: Should we adjust the D-Dimer cut-off for age? - CanadiEM
    Posted at 22:37h, 01 October Reply

    […] Rezaie (@srrezaie) of REBEL:EM, Rory Spiegel (@EMNerd_) of EMNerd, Ryan Radecki (@emlitofnote) of EMLitofNote, and Andy Neill […]

  • Tony Morris, M.D., Pathology
    Posted at 22:16h, 02 February Reply

    Has any ER and their local laboratory actually implemented this? Our E.R. physicians are interested.
    Thanks,
    Tony
    Red Deer, Alberta

  • Jeremy
    Posted at 11:14h, 24 November Reply

    How can I do this if my lab assay for d-dimer cutoff is .249 instead of .500? Do I just multiply by 5? Is there any validation to this?

    • Jeremy
      Posted at 11:17h, 24 November Reply

      Sorry our number is actually <230 so it's a little more complicated

      • Salim Rezaie
        Posted at 11:43h, 24 November Reply

        Hello Jeremy,
        Great question. As far as I know the studies have only looked at the quantitative D-Dimers with cut-offs of 500ug/L. I have heard some people will multiply by 2 if their cutoff is 250, but that is not evidence based. Currently best evidence is to use assays that are quantitative and have a 500g/L cutoff. Hope this helps.

        Salim

  • syncopal PE’s, gestalt, & sensationalism. | EM in Focus
    Posted at 16:10h, 20 October Reply

    […] a part of a syncopal work up, and probably for the “near syncopal” as well.  But what about age-adjusted dimers? A potential role can & should be seen here for those of us with concern enough to send a […]

Post A Comment

Time limit is exhausted. Please reload CAPTCHA.