You are working in a community ED one afternoon when you encounter Mrs. X, a pleasant 65-year old woman with a history of hypertension and osteoporosis, who is in town visiting her grandchildren from California. She flew in 2 days earlier, and for the last 12 hours has noted some right-sided, pleuritic chest pain. She thinks she pulled a muscle picking up her 3-year old grandson, but was worried and wanted to be evaluated.
Her physical exam is unremarkable, including a heart rate of 70, a normal oxygen saturation on room air, and a normal respiratory rate. Her lungs are clear and she does seem to have pain with deep inspiration. There is no chest wall tenderness, no LE swelling, no LE cords, and no calf tenderness.
Given her recent plane trip you are concerned about a possible PE. Having attended a journal club on reducing PE protocol CT ordering rates during residency, you calculate her Well’s score and find that she is low risk, so order a D-dimer in addition to an ECG and chest x-ray. The ECG and CXR are normal, but the D-dimer is elevated at 600 mcg/mL FEU. You explain to the patient that she will need to have a CT scan to evaluate for a PE, at the same time remembering that you’ve heard about age-adjusted D-dimer. You wonder if you could adjust the upper limits of normal for this patient, given her age, and hence obviate the need for the CT.
Too busy to look this up now, you continue your shift. The CT comes back negative and you discharge the patient on NSAIDs, but after your shift, you decide to look more closely at the evidence.
Population: Patients aged > 50 years with a clinical suspicion of PE and non-high pre-test probability.
Intervention: An age-adjusted D-dimer cutoff.
Comparison: A conventional D-dimer cutoff.
Outcome: Sensitivity, specificity, likelihood ratio, false negative rate, and decrease in additional confirmatory testing (CT, VQ scan).
PubMed was searched using the terms “age adjusted d-dimer” (http://tinyurl.com/jfa4t62). This resulted in 148 articles, from which the following 4 were selected.
Article 2: 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 May 3;346:f2492.
Article 3: 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. Ann Emerg Med. 2016 Feb;67(2):249-57.
Article 4: Douma RA, le Gal G, Sohne 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 Mar30;340:c1475.
In patients who are not high-risk for pulmonary embolism, D-dimer has been shown to be effective at ruling out disease. Unfortunately, this test also has a low specificity and a high false-positive risk. This risk increases (and specificity decreases) substantially with increasing age. The specificity decreases incrementally with each decade increase in age, from around 67% in patients < 50 years of age to nearly 15% in those over 80 (Schouten 2013). As a result, some have proposed adjusting the D-dimer cutoff based on age. A derivation study using prospective cohorts of 1721 patients from Switzerland and France determined that the Age (years) * 10 µg/L was the optimal cutoff for patients over 50 (Douma 2010). This formula assumes the use of an assay that reports results in fibrinogen equivalence units (FEU) with a standard cutoff of 500 µg/L. This same study attempted to validate this formula in two similar European patient cohorts, resulting in 11.2% (95% CI 9.3-13.3%) and 18.2% (95% CI 15-21.4%) increases in the number of patients with a negative D-dimer in each of the cohorts, with very small increases in the rates of missed PE (0.4% and 0.2%, respectively). The major limitation of this study was that all of the cohorts were comprised of fairly homogenous Western European patients.
A retrospective study conducted using medical records from Kaiser Permanente Southern California (Sharp 2016) demonstrated an increase in the specificity of D-dimer in patients over 50 years of age from 54.4% (95% CI 53.9-55.0) using the standard cutoff to 63.9% (95% CI 63.4-64.5) using this age-adjusted cutoff. While this was accompanied by a decrease in sensitivity from 98.0% (95% CI 96.4-84.2) to 92.9% (95% CI 90.3-95.0), the overall negative likelihood ratio of the age-adjusted cutoff was 0.11 (95% CI 0.08-0.15) suggesting a significant ability to rule out disease in non-high risk patients. A systematic review and meta-analysis demonstrated an even better ability to rule out PE, with a negative likelihood ratio of 0.05 in patients over 50 years of age (Schouten 2013). The primary limitation of this meta-analysis was the significant risk of verification bias in all but one of the included studies.
Having thus been derived and validated in several different populations, the age-adjusted cutoff has also been evaluated in clinical practice (Righini 2014). In a study conducted at 19 hospitals in 4 countries in Europe (Belgium, France, Switzerland, and the Netherlands), the use of an age-adjusted cutoff resulted in an absolute decrease in the number of patients requiring additional testing of 11.6% (95% CI 10.5-12.9). Out of 331 patients with a D-dimer between the conventional cutoff and the age-adjusted cutoff, only one was later found to have a venous thromboembolism, for an overall failure rate of 0.3% (95% CI 0.1-1.7).
The use of an age-adjusted cutoff has therefore been shown to significantly reduce the need for further confirmatory testing in non-high patients, thereby reducing the risks associated with CT scanning (e.g. contrast-induced nephropathy [Mitchell 2010]). Unfortunately, this comes with a small, but not insignificant increase in the false negative risk, increasing the likelihood of missing a PE. Given the medicolegal atmosphere in this country, it will likely take some work to change clinical practice on a broad scale. The current clinical practice guidelines form the American College of Emergency Physicians (ACEP) makes only brief mention of adjusting the D-dimer cutoff for age, and does not make any recommendations regarding this practice. In order to change practice, there will likely need to be some support from our professional societies in this regard, as well as support from hospitals and physicians on other services (i.e. pulmonology, critical care, internal medicine, and hospitalists).
Finally, there are multiple D-dimer assays currently available using e a wide range of cutoff values to defined “normal” and “elevated” levels. Barnes-Jewish hospital currently uses the HemosIL D-dimer with an abnormal cutoff of 230 µg/L, which makes it difficult to adjust for age using the standard formula. Standardization of these assays, or the derivation of an age-adjusted cutoff for each assay, will therefore be necessary before we can adjust our concepts of normal and abnormal at institutions that do not use an assay with a cutoff of 500 µg/L.