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Age-Adjusted D-dimer Cutoff for Reducing CT Pulmonary Angiography Tests in Elderly Patients With Suspected Pulmonary EmbolismAge-Adjusted D-dimer Cutoff for Pulmonary Embolism: Improvement or Restoration Back to Normal? FREE TO VIEW

Geert-Jan Geersing, MD, PhD
Author and Funding Information

From the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht.

CORRESPONDENCE TO: Geert-Jan Geersing, MD, PhD, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands; e-mail: g.j.geersing@umcutrecht.nl


FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(6):1423-1424. doi:10.1378/chest.14-1249
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In a famous paper from the late 1970s, Robin1 postulated his concerns about overdiagnosis and overtreatment of pulmonary embolism (PE), stating that “the emperor of embolism may have no clothes.” He was mainly concerned about overdiagnosing PE in previously healthy young women, arguing that the prior probability of PE is low in these patients, and this subsequently results in a lower positive predictive value of perfusion scans (following Bayes’ theorem). Today, concerns about overdiagnosing PE still remain highly relevant.2 However, in addition to concerns about overdiagnosing PE in young adults, current research also focuses on referring (thus, also overdiagnosing) frail elderly patients too often or too soon for suspected PE: The naked emperor of embolism is aging. The main reason behind this problem comes from the fact that D-dimer testing yields more false-positive results in the elderly as compared with a non-aged population. Thus, many patients need to be referred, and typically only 10% to 15% of these patients have confirmed PE. The use of an age-adjusted cutoff for D-dimer testing (age × 10 in those aged > 50 years) has been proposed, aiming to reduce this number of false-positive results and, thus, the number of patients for whom imaging (CT pulmonary angiography [CTPA]) is required to confirm or refute the diagnosis.3

In this issue of CHEST, Woller et al4 (see page 1444) further expand the evidence behind this so-called age-adjusted cutoff for D-dimer testing. They used a previously described impressive cohort of 3,500 patients with suspected PE5 and identified a subset of 934 patients aged > 50 years combined with a low risk of acute PE (using a Revised Geneva Score ≤ 10). All patients underwent CTPA to confirm or refute a diagnosis of PE. Among these 935 patients, 273 patients (29%) had a D-dimer value below this age-adjusted cutoff. During 90 days of follow-up, only four patients were diagnosed with PE, yielding a failure rate of 1.5% “missed” PE cases (95% CI, 0.4%-3.7%). If the conventional cutoff (< 500 ng/mL) had been used, only 104 patients (11%) had a negative D-dimer, yet in this group no PE cases were missed. Thus, they demonstrated an almost 20% reduction of required CTPA tests for this age-adjusted cutoff, as compared with the conventional cutoff. These findings—a sharp reduction in CTPA tests at the cost of a slightly higher failure rate—are largely in concurrence with previous studies, including a recent meta-analysis (not yet including the current article from Woller et al4) on this age-adjusted D-dimer cutoff.6

Now, the question arises: Would this higher failure rate (still) be acceptable in the context of fewer CTPA tests in these elderly patients? Basically, this comes back to answering the following two questions. First, how many additional PE cases are missed, and how many of them are fatal? Second, how many CTPA tests are avoided? This is important as at least in some patients CTPA will be performed without PE being present, and these patients are at risk for unnecessary iatrogenic damage from CTPA (including radiation and contrast nephropathy). Ideally, these questions should be addressed in a formal randomized controlled trial (RCT) comparing both diagnostic strategies. However, RCTs comparing diagnostic strategies are in general difficult to perform (as well as to finance) and for now are lacking. Indirect comparisons may, however, be more feasible. For instance, if we compare aggregated data from an also recently published prospective evaluation of the age-adjusted cutoff (the ADJUST-PE study7), plus the study by Woller et al,4 with a landmark and large-scale diagnostic management study in suspected PE using a conventional cutoff (the Christopher Study8), the following conclusions can be drawn (Table 1). First, using either a conventional or an age-adjusted cutoff, the proportion of missed PE cases is comparable and small (well below 2%), and no fatal cases occur, which is a reassuring finding. Second, more strikingly, the proportion of patients for whom CTPA is still required is also rather comparable: Still around six to seven in every 10 suspected patients require CTPA to confirm or refute a diagnosis of PE, a finding in concurrence with a systematic review on decision rules in suspected PE.9 This leaves us startled. Comparisons within cohorts demonstrate a sharp reduction of required CTPA tests, notably in the eldest elderly. Yet, an indirect comparison over different cohorts does not demonstrate this reduction of CTPA tests. Obviously, inherent problems related to this indirect (nonrandomized) comparison play a role here. Combing individual patient data (IPD) of these studies and using state-of-the-art IPD meta-analysis10 could allow us to explain these different findings between within and over cohort comparisons. For instance, the number of comorbidities, the applied clinical decision rule, the prevalence of PE in different studies, increasing age, D-dimer assay used, as well as the applied reference standard (as over time CTPA has become increasingly more sensitive in finding smaller emboli) could all be evaluated as potential modifiers of the safety and efficiency of this age-adjusted D-dimer. This would provide us valuable information on the subgroup of patients that benefit most from using this age-adjusted cutoff.

Table Graphic Jump Location
TABLE 1 ]  An Indirect Comparison Between Using a Conventional or Age-Adjusted Cutoff for D-dimer Testing

None of the missed PE cases were fatal PE. Both the ADJUST-PE and the study by Woller et al4 evaluated the age-adjusted cutoff for D-dimer testing; the Christopher Study evaluated the use of a conventional cutoff. The ADJUST-PE study is the only currently available prospective evaluation. Moreover, in the evaluation by Woller et al,4 only patients ≥ 50 y are included, whereas in both the Christopher and the ADJUST-PE studies patients < 50 y are also included. CTPA = CT pulmonary angiography; PE = pulmonary embolism.

To summarize, the use of an age-adjusted cutoff for D-dimer testing seems to be a promising and safe tool in patients with suspected PE, and the current study by Woller et al4 reaffirms this finding also in older patients. One of the most promising aspects includes the possibility of reducing the number of CTPA tests required in frail elderly and, thus, also iatrogenic damages (and costs) caused by CTPA. This comes at the cost of a small (negligible) increase of missed PE cases. A formal randomized comparison between the age-adjusted and the conventional cutoff for D-dimer testing is preferable to confirm these findings. Yet—before we embark on such a costly and difficult RCT—first more indirect comparisons can be done using IPD meta-analysis, allowing us to better appreciate the potentially huge merits of this age-adjusted cutoff in various subgroups of elderly patients with suspected PE.

References

Robin ED. Overdiagnosis and overtreatment of pulmonary embolism: the emperor may have no clothes. Ann Intern Med. 1977;87(6):775-781. [CrossRef] [PubMed]
 
Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171(9):831-837. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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(6):1444-1451.
 
Adams DM, Stevens SM, Woller SC, et al. Adherence to PIOPED II investigators’ recommendations for computed tomography pulmonary angiography. Am J Med. 2013;126(1):36-42. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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(11):1117-1124. [CrossRef] [PubMed]
 
van Belle A, Büller HR, Huisman MV, et al; Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172-179. [CrossRef] [PubMed]
 
Lucassen W, Geersing GJ, Erkens PM, et al. Clinical decision rules for excluding pulmonary embolism: a meta-analysis. Ann Intern Med. 2011;155(7):448-460. [CrossRef] [PubMed]
 
Debray TP, Moons KG, Abo-Zaid GM, Koffijberg H, Riley RD. Individual participant data meta-analysis for a binary outcome: one-stage or two-stage? PLoS ONE. 2013;8(4):e60650. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
TABLE 1 ]  An Indirect Comparison Between Using a Conventional or Age-Adjusted Cutoff for D-dimer Testing

None of the missed PE cases were fatal PE. Both the ADJUST-PE and the study by Woller et al4 evaluated the age-adjusted cutoff for D-dimer testing; the Christopher Study evaluated the use of a conventional cutoff. The ADJUST-PE study is the only currently available prospective evaluation. Moreover, in the evaluation by Woller et al,4 only patients ≥ 50 y are included, whereas in both the Christopher and the ADJUST-PE studies patients < 50 y are also included. CTPA = CT pulmonary angiography; PE = pulmonary embolism.

References

Robin ED. Overdiagnosis and overtreatment of pulmonary embolism: the emperor may have no clothes. Ann Intern Med. 1977;87(6):775-781. [CrossRef] [PubMed]
 
Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171(9):831-837. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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(6):1444-1451.
 
Adams DM, Stevens SM, Woller SC, et al. Adherence to PIOPED II investigators’ recommendations for computed tomography pulmonary angiography. Am J Med. 2013;126(1):36-42. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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(11):1117-1124. [CrossRef] [PubMed]
 
van Belle A, Büller HR, Huisman MV, et al; Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172-179. [CrossRef] [PubMed]
 
Lucassen W, Geersing GJ, Erkens PM, et al. Clinical decision rules for excluding pulmonary embolism: a meta-analysis. Ann Intern Med. 2011;155(7):448-460. [CrossRef] [PubMed]
 
Debray TP, Moons KG, Abo-Zaid GM, Koffijberg H, Riley RD. Individual participant data meta-analysis for a binary outcome: one-stage or two-stage? PLoS ONE. 2013;8(4):e60650. [CrossRef] [PubMed]
 
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