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Original Investigation
December 7, 2021

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

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
JAMA. 2021;326(21):2141-2149. doi:10.1001/jama.2021.20750
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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