Age-Adjusted D-dimer: Is it Ready for Prime Time?

Author: Courtney Cassella, MD (EM Resident Physician, Icahn School of Medicine at Mount Sinai) // Edited by: Alex Koyfman, MD (EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital, @EMHighAK) & Justin Bright, MD (@JBright2021)

Background

Pulmonary embolism is a life-threatening entity affecting up to 900,000 individuals a year.1 Per ACEP Clinical policy2, there is level B evidence the Wells score3-5, Revised Geneva score6-8, or clinical gestalt8, 9 may be used to risk stratify patients with suspected PE.  In low pretest probability patients, PERC10, 11 may be utilized to exclude PE by H&P alone (level B).

(For a more thorough discussion of the PERC rule, see PERC Rule: Application and Limitations by Jason West.12  http://www.emdocs.net/perc-rule-application-limitations/)

Alternatively, there is level A evidence a negative D-dimer can be used to exclude PE in these low pretest probability patients.  Furthermore, level C evidence states a negative D-dimer in the intermediate risk group can exclude PE. 2, 13

Unfortunately, D-dimer levels increase with age decreasing the yield of the test. In order to increase the specificity safely, Douma et al. performed a retrospective analysis to derive age-adjusted D-dimer cutoffs. The study developed the age-adjusted D-dimer with a receiver operating characteristics (ROC) curve.14 In JAMA 2014, Righini et al. published a prospective study utilizing the age-adjusted cutoff.

AGE ADJUSTED D-DIMER CUTOFF = (AGE X 10) μg/L
**Applies to 50+ years old

THE PROSPECTIVE STUDY:

Age-Adjusted D-dimer Cutoff Levels to Rule out Pulmonary Embolism: The ADJUST-PE Study by Righini et al., JAMA 2014 15

METHODS

A multicenter, multinational (Belgium, France, Netherlands and Switzerland) prospective study involving 19 hospitals from January 2, 2010 to February 28, 2013. There were 3346 participants.

Inclusion criteria: Patients with a clinical suspicion of PE defined as acute onset or worsening shortness or breath or chest pain without an obvious etiology.

Exclusion criteria:

  • Suspicion for PE after 24 hours after admission
  • On anticoagulation for another indication (e.g. atrial fibrillation)
  • Contraindication to CTPA
    • Allergy to contrast
    • Impaired renal function (Cockcroft-Gault creatinine clearance <30mLmin)
  • Life expectancy less than 3 months
  • Ongoing pregnancy
  • Inaccessibility for follow-up
  • Study Design:

Patients were risk stratified using 2-Level Wells or the Revised Geneva Score. Patients who fell into the PE unlikely or non-high clinical probability group were tested with a D-dimer. Those with D-dimers beneath the age-adjusted cut-off were discharged and followed-up 3 months later.

study design

Primary outcome: Symptomatic thromboembolic events during 3-month follow-up period among patients not treated on the basis of negative age-adjusted D-dimer.

Venous Thromboembolic Events

  • DVT – ultrasound
  • PE
    • V/Q scan with high-probability pattern
    • CTPA or angiography with segmental or proximal intraluminal defects

Blinded experts adjudicated suspected VTEs and deaths.

Secondary outcome: Symptomatic thromboembolic events during 3-month follow-up period in low-intermediate or unlikely probability with D-dimer between 500µg/L and age-adjusted cutoff.

RESULTS

Of the 3346 patients with suspected PE, the overall prevalence of PE was 19%.

2 chart

There were 2898 with unlikely or non-high clinical probability of PE.

  • 817 (28.2%) D-dimer <500µg/L
    • 3-month follow-up:
      • 810 eligible
      • 2 deaths and 8 suspected VTE
      • 1 confirmed nonfatal PE (1% missed)
  • 337 (11.6%) D-dimer between 500ug/L and age-adjusted cutoff
    • 3-month follow-up:
      • 331 eligible
      • 7 deaths and 7 suspected VTE
      • 1 confirmed nonfatal PE (3% missed)

D-dimer >age-adjusted cutoff, likely or high clinical probability

  • 1539 had a negative CTPA.
    • 3-month follow-up:
      • 1481 eligible
      • 18 deaths and 40 suspected VTE
      • 7 VTEs à failure rate in negative CTPA is 0.5%

766 patients were 75 years or older, 673 (87.9%) had a non-high clinical probability of PE. Using the age-adjusted cutoff, the number of D-dimer negative patients increased from 6.4% to 29.7%. None of these patients had a confirmed VTE.

Support

Subsequently, at least seven studies have investigated age-adjusted D-dimer (Polo Friz et al.16, Woller et al.17, Gupta et al.18, Flores et al.19, Han et al.,20 Altman et al.21, and Sharp et al.22). Although each has its limitations, the literature indicates age-adjusted D-dimer would decrease imaging with acceptable miss rates.

table

Ultimately, age-adjusted D-dimer aims to increase specificity and therefore decrease unnecessary imaging. Gupta et al. found applying the age-adjusted threshold, did not significantly compromise sensitivity while avoiding 52 CTPAs (18.2%) in patients older than 50 years with a low risk Wells score.18 Sharp et al. found although the sensitivity was slightly diminished (ADD 93% vs. CDD 98%), age-adjusted D-dimer would prevent 322 cases of contrast-induced nephropathy, 29 cases of severe renal failure, and 19 deaths related to contrast-induced nephropathy.22

Conclusions

A meta-analysis by Schouten et al. reviewed 13 retrospective studies (12,497 patients) investigating age-adjusted D-dimer published before June 21, 2012.  All studies analyzed patients with non-high clinical probability scores. The pooled sensitivity of age-adjusted D-dimer was 97% or above for all age categories. Specificity was improved with the age-adjusted D-dimer in all age groups.23

table 2

Age-adjusted D-dimer has been investigated in retrospective and some prospective studies. Although prospective trials are rare and no recent meta-analysis or clinical policy statement has been issued, there is an abundance of evidence that age-adjusted D-dimer increases specificity with minimal and acceptable decline in sensitivity in the low risk population.

 

FYI

AGE ADJUSTED D-DIMER CUTOFF = (AGE X 10) μg/L
**Applies to 50+ years old

fyi

References/Additional Reading

  1. Church A, Tichauer M. The emergency medicine approach to the evaluation and treatment of pulmonary embolism. Emergency medicine practice. 2012;14(12):1-22.
  2. Fesmire FM, Brown MD, Espinosa JA, Shih RD, Silvers SM, Wolf SJ, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Annals of emergency medicine. 2011;57(6):628-652 e675.
  3. van Belle A, Buller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172-179.
  4. Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Annals of internal medicine. 2001;135(2):98-107.
  5. Wolf SJ, McCubbin TR, Feldhaus KM, Faragher JP, Adcock DM. Prospective validation of Wells Criteria in the evaluation of patients with suspected pulmonary embolism. Annals of emergency medicine. 2004;44(5):503-510.
  6. Klok FA, Kruisman E, Spaan J, Nijkeuter M, Righini M, Aujesky D, et al. Comparison of the revised Geneva score with the Wells rule for assessing clinical probability of pulmonary embolism. Journal of thrombosis and haemostasis : JTH. 2008;6(1):40-44.
  7. Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Annals of internal medicine. 2006;144(3):165-171.
  8. Penaloza A, Verschuren F, Meyer G, Quentin-Georget S, Soulie C, Thys F, et al. Comparison of the unstructured clinician gestalt, the wells score, and the revised Geneva score to estimate pretest probability for suspected pulmonary embolism. Annals of emergency medicine. 2013;62(2):117-124 e112.
  9. Ceriani E, Combescure C, Le Gal G, Nendaz M, Perneger T, Bounameaux H, et al. Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis. Journal of thrombosis and haemostasis : JTH. 2010;8(5):957-970.
  10. Kline JA, Courtney DM, Kabrhel C, Moore CL, Smithline HA, Plewa MC, et al. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. Journal of thrombosis and haemostasis : JTH. 2008;6(5):772-780.
  11. Kline JA, Mitchell AM, Kabrhel C, Richman PB, Courtney DM. Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. Journal of thrombosis and haemostasis : JTH. 2004;2(8):1247-1255.
  12. West J. PERC Rule: Application and Limitations. http://www.emdocs.net/perc-rule-application-limitations/. Published 2015. Accessed Sept 26, 2015.
  13. Carrier M, Righini M, Djurabi RK, Huisman MV, Perrier A, Wells PS, et al. VIDAS D-dimer in combination with clinical pre-test probability to rule out pulmonary embolism. A systematic review of management outcome studies. Thrombosis and haemostasis. 2009;101(5):886-892.
  14. Douma RA, le Gal G, Sohne M, Righini M, Kamphuisen PW, Perrier A, 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;340:c1475.
  15. Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA. 2014;311(11):1117-1124.
  16. Polo Friz H, Pasciuti L, Meloni DF, Crippa M, Villa G, Molteni M, et al. A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients. Thrombosis research. 2014;133(3):380-383.
  17. Woller SC, Stevens SM, Adams DM, Evans RS, Lloyd JF, Snow GL, et al. Assessment of the safety and efficiency of using an age-adjusted D-dimer threshold to exclude suspected pulmonary embolism. Chest. 2014;146(6):1444-1451.
  18. Gupta A, Raja AS, Ip IK, Khorasani R. Assessing 2 D-dimer age-adjustment strategies to optimize computed tomographic use in ED evaluation of pulmonary embolism. The American journal of emergency medicine. 2014;32(12):1499-1502.
  19. Flores J, Garcia de Tena J, Galipienzo J, Garcia-Avello A, Perez-Rodriguez E, Tortuero JI, et al. Clinical usefulness and safety of an age-adjusted D-dimer cutoff levels to exclude pulmonary embolism: a retrospective analysis. Internal and emergency medicine. 2015.
  20. Han C, Zhao Y, Cheng W, Yang J, Yuan J, Zheng Y, et al. The performance of age-adjusted D-dimer cut-off in Chinese outpatients with suspected venous thromboembolism. Thrombosis research. 2015.
  21. Altmann MM, Wrede CE, Peetz D, Hohne M, Stroszczynski C, Herold T. Age-Dependent D-dimer Cut-off to Avoid Unnecessary CT-Exams for Ruling-out Pulmonary Embolism. RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. 2015;187(9):795-800.
  22. Sharp AL, Vinson DR, Alamshaw F, Handler J, Gould MK. An Age-Adjusted D-dimer Threshold for Emergency Department Patients With Suspected Pulmonary Embolus: Accuracy and Clinical Implications. Annals of emergency medicine. 2015.
  23. Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA, 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;346:f2492.

 

6 thoughts on “Age-Adjusted D-dimer: Is it Ready for Prime Time?”

  1. It’s now part of the ACP’s clinical policy best practices:
    Ann Intern Med. 2015 Nov 3;163(9):701-11. doi: 10.7326/M14-1772. Epub 2015 Sep 29. Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Raja AS, et al.

  2. It’s now part of the ACP’s clinical policy best practices:
    Ann Intern Med. 2015 Nov 3;163(9):701-11. doi: 10.7326/M14-1772. Epub 2015 Sep 29. Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Raja AS, et al.

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