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Three Part Question

In [patients with signs and symptoms of pulmonary embolism who are deemed low risk] is a [age adjusted D-dimer sensitive enough] compared to a standard D-dimer to [safely exclude pulmonary embolism]?

Clinical Scenario

A70 year old man presents with pleuritic chest pain. A D-dimer taken at triage is mildly elevated from the standard positive threshold. You feel he is at low risk of pulmonary embolism based on his wells score, and proceed to CTPA. CTPA shows no evidence of pulmonary embolism. You wonder whether an age adjusted D-dimer level would have excluded PE in this gentleman without the need for further investigations.

Search Strategy

Using Pubmed database 1966 to week 1 December 2014.
("pulmonary embolism"[MeSH Terms] OR ("pulmonary"[All Fields] AND "embolism"[All Fields]) OR "pulmonary embolism"[All Fields]) AND ("fibrin fragment D"[Supplementary Concept] OR "fibrin fragment D"[All Fields] OR "d dimer"[All Fields]) AND ("Age"[Journal] AND adjusted[All Fields]

Search Outcome

29 unique papers of which 13 included data on patients relevant to the clinical question (12 in English and 1 in German)

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Woller et al 2014 USA	923 patients aged older than 50 years with suspected PE	Retrospective review of patient records	Revised Geneva Score (RGS), D-dimer level and CTPA result	In patients aged over 50 years the use of a conventional D-dimer threshold yielded 104 negative D-dimer results (11.3%) When an age adjusted D-dimer threshold is used (age x 10ng/ml) this results in 273 negative D-dimer results (29.6%)	Retrospective study Risk of misclassification bias in calculation of RGS
Vossen et al 2012 USA	237 consecutive patients with suspected PE	Retrospective review of patient records	D-dimer level and CTPA result	In patients aged over 50 years the use of a conventional D-dimer threshold (500µg/L):- Sensitivity-100% (95% CI, 31-100%) Specificity-5% (95% CI, 2-10%) Increasing the threshold to 2000µg/L:- Sensitivity-100% (95% CI, 31-100%) Specificity-81% (95% CI, 73-87%)	Retrospective analysis Limited to community hospital setting
Righini et al 2014 Switzerland	3346 patients with suspected PE	Multicentre, multinational, prospective management outcome study	Revised Geneva score or the 2-level Wells score for PE; D-dimer level and CTPA result	In patients 75 years or older using conventional cut-off of 500µg/L PE could be excluded in 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) and with the age-adjusted cutoff (age x 10µg/) 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%) could be excluded without any additional false-negative findings.	Multiple D-dimer assays used
Laruelle et al 2013 Belgium	165 patients older than 75 with suspected PE	Retrospective chart review	Pulmonary scintigraphy and/or CTPA and D-dimer level	In patients older than 75 using a standard D-dimer threshold:-Specificity-6% Sensitivity-98% Using an age adjusted (age x0.01µg/ml) threshold:-Specificity-23% Sensitivity-96%	Retrospective study
Schouten et al 2013 Netherlands	12497 patients (from 13 cohorts) with a non-high clinical probability of VTE	Systematic review and bivariate random effects meta-analysis	D-dimer level	In patients older than 80 using a standard D-dimer threshold:-Specificity-14.7% (95% CI, 11.3-18.6%) Using an age adjusted (age x10µg/L) threshold:- Specificity-35.2% (95% CI, 29.4-41.5%)	Multiple D-dimer assays used Multiple different reference standards Included studies looking at patients with suspected DVT
Polo Friz et al 2014 Italy	481 patients with suspected PE	Retrospective cohort study	D-dimer and CTPA	In patients older than 80 using a standard D-dimer threshold (490ng/L):-Sensitivity-100% (95% CI, 90.5-100%) Specificity-0.0% (95% CI, 0.0-2.4%) Using an age-adjusted D-dimer threshold (age x 10ng/ml):-Sensitivity-100% (95% CI, 90.5-100%) Specificity-6.5% (95% CI, 2.6-10.4%)	Retrospective study
Leng et al 2012 UK	528 patents who underwent CTPA scanning for suspected PE	Retrospective review of notes	D-dimer and CTPA	In patients >50 years old who underwent CTPA, 22 (5.2%) of 423 had D-dimer concentrations higher than the traditional threshold but lower than the age-adjust threshold (age in years x 10), none of whom had evidence of PE on CTPA. No patient with a D-dimer concentration below the age adjusted threshold had a PE confirmed by CTPA.	Retrospective study
Penaloza et al 2012 Belgium	4537 patients with suspected PE	Secondary analysis of three prospectively collected of patients suspected of having PE	D-dimer level	In patients over 50 years using a standard D-dimer threshold (500µg dL-1):-False negative rate 0.6% (95% CI, 0.3-1.0%) Age adjusted D-dimer cut off (age x 10 in patients over 50 years):- False negative rate 0.8% (95% CI, 0.5-1.2%) The false negative rate increased in patients over 75 years 3.9% (95% CI, 1.6-7.9%)	Secondary analysis of prospective studies Included studies analysing DVT
Douma et al 2010 Netherlands	5132 consecutive patients with suspected PE	Retrospective multicentre cohort study	Proportion of patients in the validation cohorts with a negative D-dimer test	In patients aged over 50 years, using the standard cut-off value of 500 µg/L PE could be excluded in 36% of cases and using the age adjusted D-dimer value (age×10μg/l) it could be excluded in 42% of cases.	Multiple D-dimer assays Retrospective analysis
Rowe et al 2013 USA	5556 patients who had D-dimer performed for suspected VTE	Retrospective chart review	D-dimer level, CTPA	Of the total number of patients 810 had a positive D-dimer level using the traditional threshold and subsequent imaging showed only 26 had VTE. Out of these 810 patients, 130 would have tested negative with an age adjusted threshold (age x 0.01ng/ml), only 4 had VTE of this group.	Retrospective study
Gupta et al 2014 USA	3063 patients with suspected PE	Retrospective study	CTPA and d-dimer	In patients older than 60 using a standard D-dimer threshold (500ng/L):-Sensitivity-100% (95% CI, 94.2-100%) Specificity-7.4% (95% CI, 5.8-9.2%) Using a decade age-adjusted D-dimer threshold (600ng/L for 61-70, 700ng/L for 71-80 etc):-Sensitivity-98.7% (95% CI, 92.1-99.9%) Specificity-13.5% (95% CI, 12.2-16.8%) Using a yearly age-adjusted D-dimer threshold (age in years x 10ng/ml):-Sensitivity-97.4% (95% CI, 90.2-99.6%) Specificity-16.7% (95% CI, 14.4-19.2%)	Retrospective study
Van Es et al 2012 Amsterdam	414 consecutive patients with suspected PE who were older than 50 years	Analysis of prospective cohort study	D-dimer test, Wells score, Revised Geneva Score (RGS), simplified Wells score and simplified RGS	In patients above 50 years, a normal age-adjusted D-dimer level (age x 10µg/l) substantially increased the number of patients in whom PE could be safely excluded from 13-14% to 19-22%. In patients over 70 years, the number of exclusions was nearly four-fold higher	Analysed retrospectively Small data set Wide CIs of false negative rate Different D-dimer assays
Verma et al 2013 Germany	1033 patients with suspected VTE	Retrospective cohort study	D-dimer	Using the conventional cut-off of 0.5 mg/dl, PE could be excluded in 68% of patients. Using the age-adjusted cut-off (age ×0.016) mg/l) PE could be ruled out in 77% of pa¬tients. In patients >70 years, the negative prediction accuracy of excluding a PE/DVT increased explicitly. The failure rate of the age-adjusted value was 0.8% (95%CI, 0.3-1.6%)	Retrospective study Wide confidence interval of age adjusted cut-off value 0.3-1.6%

Comment(s)

It is established knowledge that D-dimer, the fibrin degradation product, increases with age. Despite this many institutions use a fixed D-dimer level regardless of a patient's age. In patients with a low pretest probability of pulmonary embolism based on the Wells score or revised Geneva score, clinicians then proceed to a D-dimer blood test. If this is positive then imaging has to be performed, generally CTPA. This carries with it a risk of contrast-induced nephropathy and the economic impact of imaging costs and in-patient care. The above studies uniformly show that an age-adjusted D-dimer increases specificity with similar sensitivity rates in low risk patients suspected of having PE. This benefit increases with age. The threshold for the use of an age adjusted value differed between studies but were all at least above 50 years of age.

Clinical Bottom Line

In older patients suspected of having a PE, with a low pretest possibility, an age-adjusted D-dimer increases specificity with minimal change in the sensitivity, thereby increasing the number of patients who can be safely discharged without further investigations.

References

1. Woller SC, Stevens SM, Adams DM et al. Assessment of the safety and efficiency of using an age-adjusted d-dimer threshold to exclude suspected pulmonary embolism Chest. 2014;146:1444–51.
2. Vossen JA, Albrektson J, Sensarma A, et al. Clinical usefulness of adjusted D-dimer cut-off values to exclude pulmonary embolism in a community hospital emergency department patient population Acta Radiol. 2012;53:765–8.
3. 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;311:1117–24. Erratum in: JAMA. 2014;311(16):1694.
4. Laruelle M, Descamps OS, Lesage V. D-dimer cut-off adjusted to age performs better for exclusion of pulmonary embolism in patients over 75 years. Acta Clin Belg. 2013;68:298–302.
5. 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 BMJ. 2013;346:f2492.
6. Polo Friz H, 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;133:380–3.
7. Leng O, Sitaraaman HB Application of age-adjusted D-dimer threshold for exclusion thromboembolism (PTE) in older patients: a retrospective study Acute Med. 2012;11:129-32.
8. 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;10:1291–6.
9. Douma RA, le Gal G, Söhne M, 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.
10. Rowe JC, Marchick MR Evaluation of an age-adjusted D-dimer threshold in the diagnosis of acute venous thromboembolism Academic Emergency Medicine 2013;20(Suppl 1):S104–5).
11. 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. Am J Emerg Med. 2014;32:1499–502.
12. 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. Thrombosis & Haemostasis 2012;107:167–71.
13. Verma N, Willeke P, Bicsan P, et al. Age-adjusted D-dimer cut-offs to diagnose thromboembolic events: validation in an emergency department Medizinische Klinik, Intensivmedizin Und Notfallmedizin, 2014; 109:121–8.