ADJUST-PE Study: ALiEM-Annals of EM Journal Club

We are very excited this month to bring you our fourth ALiEM-Annals of EM Global Journal Club on the use of age-adjusted D-dimer levels to help exclude the diagnosis of pulmonary embolism (PE). We hope you will participate in an online discussion of the four posted questions below from now until August 29th. Respond by commenting below or tweeting (#ALiEMJC). Mark your calendars: On Thursday, August 28th at 16:30 CST (17:30 EST), we will be hosting a 30-minute live Google Hangout with Drs. Jeff Kline and Jonathan Kirschner, the authors of the Annals of Emergency Medicine Journal Club for the ADJUST-PE Trial, that is informed by the discussion. Later this year, a summary of this journal club will hopefully be published in Annals of EM.

Google Hangout With Drs. Kline and Kirschner

Timestamps

• 00:00  Dr. Salim Rezaie launches the Google Hangout.
• 00:29  Dr. Sam Shaikh briefly reviews the ADJUST-PE study.
• 01:17  Dr. Shaikh presents question 1 about the older medan age (63 years old) of the ADJUST-PE study population.
• 01:41  Dr. Jonathan Kirschner (Indiana University-Purdue University Indianapolis) discusses spectrum bias, based on differing prevalence values, and how that may affect the generalizability of the ADJUST-PE findings.
• 03:18  Dr. Jeff Kline (Indiana University-Purdue University Indianapolis) talks about why he PE seems to behave differently in the U.S. compared to Europe.
• 04:44  Dr. Anand Swaminathan presents question 2 about the lack of uniformity of different d-dimer assays.
• 05:13  Dr. Kline gives his perspective and shares unpublished survey data on PE’s and d-dimer.
• 06:29  Dr. Kirschner elaborates on this survey data – 80% of respondents did not know what d-dimer assay they use.
• 07:32  Dr. Swaminathan identified that different d-dimer cutoffs are set by local pathologists based on whether looking at venous thromboembolism vs DIC, which adds to clinician confusion.
• 08:35  Dr. Kirschner advocates for normalized d-dimer values to avoid confusion.
• 09:07  Dr. Kline explains that hospitals run assays and set their own cutoffs, as mandated by CLIA. Advocates for a grass-roots efforts to create a normalized d-dimer, because the FDA doesn’t have the power to mandate this across diagnostic lab companies.
• 10:25  Dr. Teresa Chan asks about whether can calculate normalized d-dimers already right now. Dr. Kline answers that this is possible right now with “a little bit of work”.
• 11:45  Dr. Rezaie reviews that the prevalence of the ADJUST-PE study was 19% which is much higher than in the U.S. (5-10%). Why the discrepancy? What’s the importance? Dr. Kirschner and Dr. Kline address this question about discrepancy.
• 14:23  Dr. Rezaie introduces Dr. Anton Helman’s point from the blog comments about Canada’s PE prevalence rate (9.5%) based on earlier Wells’ study.
• 15:00  Dr. Kline notes that the prevalence rates of PE are declining worldwide. He provides his hypothesis, based on a declining rate of community-based care in Europe which typically screens out the really low risk patients.
• 17:17  Dr. Kirschner also notes that it may be a difference in “value” leading to PE prevalence with U.S. providers seemingly striving for the impossible goal of a zero-miss rate for diseases.
• 18:08  Dr. Swaminathan is also surprised that Canada’s prevalence is similar to that of the U.S.
• 18:50  Dr. Chan notes that “as the token Canadian, we LOVE our d-dimers”.
• 21:20  Dr. Swaminathan asks question 4 — would you change your practice using the age-adjusted d-dimer cutoffs?
• 21:48  Dr. Kirschner clarifies that age-adjusted d-dimer cutoffs are reasonable to use based on both this prospective ADJUST-PE and other retrospective studies.
• 23:08  Dr. Chan and Dr. Kirschner note some pitfalls in the study methodology regarding the actual sample size (is it 3000’s or 300’s?) and the low event rate. “Clinical gestalt is still king” in the workup in PE.
• 25:40  Dr. Rezaie and Dr. Kline talk about the fact that some deaths did not undergo an autopsy to definitive diagnose PE.
• 26:54  Pneumonia is the most emergent diagnosis seen on CT pulmonary angiogram (about 10%). Dr. Kline suggests that older patients likely will undergo CT to assess for the chest symptoms regardless of d-dimer.
• 27:55  Dr. Kline gives us an early peek at his proposed algorithm for the diagnosis of PE, which does include the age-adjusted d-dimer cutoff.
• 29:54  Tweets from the audience:  Dr. Swaminathan brings in some live tweets including Dr. Rick Brody‘s point also advocating for a standardized, normalized d-dimer value across assays. Dr. Minh Le Cong‘s tweet asks about whether higher d-dimer confers higher mortality.

NEW! Journal Jam with EM Cases

EM Cases now hosts Journal Jam, featuring the ALiEM-Annals Global EM Journal Club! Listen to the terrific re-mixed podcast version of this Google Hangout on Air with great additional commentaries by Dr. Anton Helman and Dr. Teresa Chan.

Click here to go directly to the Journal Jam episode!

ADJUST-PE Study and Annals of EM Journal Club Citations

Righini M et al. Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study. JAMA. Mar 2014; 311(11):1117-24. PMID: 24643601

Kirschner JM, Kline JA. Is it time to raise the bar? Age-adjusted D-dimer cutoff levels to exclude pulmonary embolism. Ann Emerg Med. 2014 Jul;64(1):86-7. PMID: 24951413.

ADJUST-PE Abstract

Importance: D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients.

Objective: To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age x 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE.

Design, Settings, and Patients: A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013.

Interventions: All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 μg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period.

Results: Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a non-high or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 μg/L (95%CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 μg/L and their age-adjusted cutoff (95%CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 μg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3%[95%CI,0.1%-1.7%]).Among the 766 patients 75 years or older, of whom 673 had a non-high clinical probability, using the age-adjusted cutoff instead of the 500 μg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4%[95%CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95%CI, 26.4%-33.3%), without any additional false-negative findings.

Conclusions and Relevance: Compared with a fixed D-dimer cutoff of 500 μg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism.

FOAM Discussion to Date on Age-Adjusted D-Dimer Testing

Featured Questions

Q1: The median age of this European study population was 63 years, which is older than most American populations tested for PE. What effect might the older population studied have on the diagnostic accuracy of the D-dimer assay? What effect might older age have on the overall findings of this study?

Q2: Although all of the D-dimer assays used in this study had the same 500 μg/L cutoff for an abnormal value, many other quantitative D-dimer assays have different cutoffs for abnormal. What is the basis of the differences in cutoffs? Can the results of this study be translated to D-dimers with different cutoffs?

Q3: In diagnostic test accuracy studies, the prevalence of disease in the study population will directly affect the derived positive and negative predictive values—so-called posttest probabilities. The prevalence of PE in this study was 19%. How does that number compare with the prevalence of PE in studies performed in other countries? How does prevalence of disease in the study population affect the sensitivity and specificity of the diagnostic strategy?

Q4: Based on this study, would you change your practice, assuming that you have one of the 6 studied D-dimer assays? For instance, you see a 60 year-old woman with a non-high pretest probability for a PE. Your D-dimer result is 590 μg/L. Would you perform a CTPA?

Please participate in the journal club by answering either on the ALiEM blog comments below or by tweeting us using the hashtag #ALiEMJC. Please denote the question you are responding to by starting your reply with Q1, Q2, Q3, or Q4.

NEW! Contest for Best Blog Comment and Tweet

We are implementing a contest for the Best Blog Quote and Best Tweet. What, emergency physicians – competitive? No… The winners will be announced in our Annals of EM publication curating this discussion.

Disclaimer: We reserve the right to use any and all tweets to #ALiEMJC and comments below in a commentary piece for an Annals of EM publication as curated conclusion piece for this global journal club.  Your comments will be attributed, and we thank you in advance for your contributions.

Author information

Salim Rezaie, MD

ALiEM Associate Editor
Clinical Assistant Professor of EM and IM
University of Texas Health Science Center at San Antonio
Founder, Editor, Author of R.E.B.E.L. EM and REBEL Reviews

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