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Venous Thromboembolism

Effect of a Diagnostic Strategy Using an Elevated and Age-Adjusted D-Dimer Threshold on Thromboembolic Events in Emergency Department Patients With Suspected Pulmonary EmbolismA Randomized Clinical Trial

Educational Objective
To understand clinical strategies for the diagnosis of pulmonary embolism.

1 Credit CME

JAMA

Published Online: December 7, 2021

Original Investigation

Article Information and Disclosures

Author Affiliations

¹Sorbonne Université, Improving Emergency Care FHU, Paris, France
²Emergency Department, Hôpital Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Paris, France
³Emergency Department, Hôpital Lariboisière, Assistance Publique–Hôpitaux de Paris, Paris, France
⁴Emergency Department, Hospital Clínic, IDIBAPS, Barcelona, University of Barcelona, Catalonia, Spain
⁵Emergency Department, Hôpital Beaujon, Assistance Publique–Hôpitaux de Paris, Clichy, France
⁶Emergency Department, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, Paris University, Paris, France
⁷Toxicology and Chemical Risks Department, French Armed Forces Biomedical Institute, Bretigny-Sur-Orges, France
⁸Emergency Department, Hôpital Avicenne, Assistance Publique–Hôpitaux de Paris, INSERM U942-MASCOT, Bobigny, France
⁹Emergency Department, University Hospital of Nancy, Université de Lorraine, UMR_S 1116, Nancy, France
¹⁰Emergency Department, Hôpital Tenon, Assistance Publique–Hôpitaux de Paris, Paris, France
¹¹Emergency Department, CHU Nantes, Nantes, France
¹²Emergency Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Universitat Autònoma de Barcelona, Catalonia, Spain
¹³Emergency Department, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
¹⁴Emergency Department, CHU Henri Mondor, INSERM U955, Assistance Publique–Hôpitaux de Paris, Paris, France
¹⁵Université de Paris, INSERM, IAME, F-75006 Paris, France
¹⁶Emergency Department, Bichat-Claude Bernard University Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
¹⁷Emergency Department, Hôpital St-Antoine, Assistance Publique–Hôpitaux de Paris, Paris, France
¹⁸Emergency Department, Centre Hospitalier de St Denis, St Denis, France
¹⁹Tours University, Emergency Medicine Department, Tours University Hospital, Tours, France
²⁰Emergency Department, University Hospital of Poitiers, Poitiers, France
²¹Emergency Department, Groupe Hospitalier Paris–St Joseph, Paris, France
²²Emergency Department, Barts Health NHS Trust, London, United Kingdom
²³Department of Clinical Pharmacology and Clinical Research Platform Paris-East (URCEST-CRC-CRB), Assistance Publique–Hôpitaux de Paris, Sorbonne University, St Antoine Hospital, Paris, France

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Key Points

Question Among emergency department patients with suspicion of pulmonary embolism (PE) not ruled out by the pulmonary embolism rule-out criteria (PERC) rule, does use of a diagnostic strategy that combines the YEARS rule and age-adjusted D-dimer threshold safely exclude the diagnosis of venous thromboembolism?

Findings In this cluster-randomized, crossover, noninferiority trial that included 1414 patients with a suspicion of PE in France and Spain, the 3-month risk of a missed thromboembolic event using the intervention diagnostic strategy, compared with a conventional strategy, was 0.15% vs 0.80%; the confidence interval of this difference did not cross the noninferiority margin of 1.35%.

Meaning Among emergency department patients with suspected PE who were PERC positive, the use of the YEARS rule combined with the age-adjusted D-dimer threshold did not lead to an inferior rate of thromboembolic events compared with a conventional diagnostic strategy.

Abstract

Importance Uncontrolled studies suggest that pulmonary embolism (PE) can be safely ruled out using the YEARS rule, a diagnostic strategy that uses varying D-dimer thresholds.

Objective To prospectively validate the safety of a strategy that combines the YEARS rule with the pulmonary embolism rule-out criteria (PERC) rule and an age-adjusted D-dimer threshold.

Design, Settings, and Participants A cluster-randomized, crossover, noninferiority trial in 18 emergency departments (EDs) in France and Spain. Patients (N = 1414) who had a low clinical risk of PE not excluded by the PERC rule or a subjective clinical intermediate risk of PE were included from October 2019 to June 2020, and followed up until October 2020.

Interventions Each center was randomized for the sequence of intervention periods. In the intervention period (726 patients), PE was excluded without chest imaging in patients with no YEARS criteria and a D-dimer level less than 1000 ng/mL and in patients with 1 or more YEARS criteria and a D-dimer level less than the age-adjusted threshold (500 ng/mL if age <50 years or age in years × 10 in patients ≥50 years). In the control period (688 patients), PE was excluded without chest imaging if the D-dimer level was less than the age-adjusted threshold.

Main Outcomes and Measures The primary end point was venous thromboembolism (VTE) at 3 months. The noninferiority margin was set at 1.35%. There were 8 secondary end points, including chest imaging, ED length of stay, hospital admission, nonindicated anticoagulation treatment, all-cause death, and all-cause readmission at 3 months.

Results Of the 1414 included patients (mean age, 55 years; 58% female), 1217 (86%) were analyzed in the per-protocol analysis. PE was diagnosed in the ED in 100 patients (7.1%). At 3 months, VTE was diagnosed in 1 patient in the intervention group (0.15% [95% CI, 0.0% to 0.86%]) vs 5 patients in the control group (0.80% [95% CI, 0.26% to 1.86%]) (adjusted difference, −0.64% [1-sided 97.5% CI, −∞ to 0.21%], within the noninferiority margin). Of the 6 analyzed secondary end points, only 2 showed a statistically significant difference in the intervention group compared with the control group: chest imaging (30.4% vs 40.0%; adjusted difference, −8.7% [95% CI, −13.8% to −3.5%]) and ED median length of stay (6 hours [IQR, 4 to 8 hours] vs 6 hours [IQR, 5 to 9 hours]; adjusted difference, −1.6 hours [95% CI, −2.3 to −0.9]).

Conclusions and Relevance Among ED patients with suspected PE, the use of the YEARS rule combined with the age-adjusted D-dimer threshold in PERC-positive patients, compared with a conventional diagnostic strategy, did not result in an inferior rate of thromboembolic events.

Trial Registration ClinicalTrials.gov Identifier: NCT04032769

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Article Information

Corresponding Author: Yonathan Freund, MD, PhD, Service d’Accueil des Urgences, 47-83 Bd de l’Hôpital, 75013 Paris, France (yonathan.freund@aphp.fr).

Accepted for Publication: November 1, 2021.

Author Contributions: Drs Freund and Simon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Freund, Philippon, Raynal, Ganansia, Bloom, Cachanado, Simon.

Acquisition, analysis, or interpretation of data: Freund, Chauvin, Jimenez, Philippon, Curac, Fémy, Gorlicki, Chouihed, Goulet, Montassier, Dumont, Lozano Polo, Le Borgne, Khellaf, Bouzid, Raynal, Abdessaied, Laribi, Guenezan, Miró, Bloom, Cachanado.

Drafting of the manuscript: Freund, Raynal, Bloom, Cachanado.

Critical revision of the manuscript for important intellectual content: Freund, Chauvin, Jimenez, Philippon, Curac, Fémy, Gorlicki, Chouihed, Goulet, Montassier, Dumont, Lozano Polo, Le Borgne, Khellaf, Bouzid, Raynal, Abdessaied, Laribi, Guenezan, Ganansia, Miró, Bloom, Simon.

Statistical analysis: Abdessaied, Cachanado.

Obtained funding: Freund, Philippon, Cachanado, Simon.

Administrative, technical, or material support: Philippon, Raynal, Laribi, Miró, Simon.

Supervision: Freund, Philippon, Ganansia, Simon.

Conflict of Interest Disclosures: Dr Laribi reported receiving personal fees from Novartis, Bristol Myers Squibb, Aspen, and AstraZeneca outside the submitted work. Dr Miró reported receiving grants from ISCIII_Spanish Ministry of Health (FIS18/00393) outside the submitted work. Dr Simon reported receiving grants from the French Ministry of Health, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Novartis, and Sanofi; personal fees from AstraZeneca, Ablative Solutions, Bayer, Novartis, Sanofi, and 4Living Biotech; and fees for conferences, counseling, and/or research grants from Merck Sharp & Dohme, Amgen, and Sanofi outside the submitted work. No other disclosures were reported.

Funding/Support: This research was funded by a grant from the French Health Ministry (Programme Hospitalier de Recherche Clinique 2017). The sponsor was the Assistance Publique–Hôpitaux de Paris.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Pierre Hausfater, MD, PhD (Assistance Publique–Hôpitaux de Paris, France), for his help and support. Dr Hausfater did not receive any compensation for his role in this study.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.