Age Adjusted D-Dimer Testing

28 Apr
April 28, 2014

ThromboembolismD-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: (20354012)
    • 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: (22568451)
    • Conclusion: Age-adjusted cut-off increased clinical usefulness of D-dimer in older patients
  • PE Validation: (22072293)
    • 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: (22674922)
    • 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: (22511491)
    • 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 (23645857) 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:

Type of D-DimerAge (years)Pooled SensitivityPooled Specificity
Conventional51 - 60100%57.6%
Conventional61 - 7099.0%39.4%
Conventional71 - 8098.7%24.5%
Conventional>8099.6%14.7%
Age Adjusted51 - 6099.4%62.3%
Age Adjusted61 - 7097.3%49.5%
Age Adjusted71 - 8097.3%44.2%
Age Adjusted>8097.0%35.2%

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? (24643601) 

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

Important MessageTake 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.

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

 

Bibliography

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Salim Rezaie

Clinical Associate Professor of EM and IM at University of Texas Health Science Center at San Antonio (UTHSCSA)
Creator & Founder of R.E.B.E.L. EM
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13 replies
  1. Per Staffan says:

    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

    Reply
    • Salim Rezaie says:

      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

      Reply
  2. Tony Morris, M.D., Pathology says:

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

    Reply
  3. Jeremy says:

    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?

    Reply
    • Jeremy says:

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

      Reply
      • Salim Rezaie says:

        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

        Reply

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