Impact of the Age-Adjusted D-Dimer Cutoff to Exclude Pulmonary Embolism
2021; Lippincott Williams & Wilkins; Volume: 143; Issue: 18 Linguagem: Inglês
10.1161/circulationaha.120.052780
ISSN1524-4539
AutoresHelia Robert‐Ebadi, Philippe Robin, Olivier Hügli, Franck Verschuren, Albert Trinh-Duc, Pierre‐Marie Roy, Jeannot Schmidt, Thierry Fumeaux, Guy Meyer, Daniel Hayoz, Pierre‐Nicolas Carron, Pierre‐Yves Salaün, François Sarasin, Olivier Rutschmann, Grégoire Le Gal, Marc Righini,
Tópico(s)Diagnosis and Treatment of Venous Diseases
ResumoHomeCirculationVol. 143, No. 18Impact of the Age-Adjusted D-Dimer Cutoff to Exclude Pulmonary Embolism Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBImpact of the Age-Adjusted D-Dimer Cutoff to Exclude Pulmonary EmbolismA Multinational Prospective Real-Life Study (the RELAX-PE Study) Helia Robert-Ebadi, MD Philippe Robin, MD Olivier Hugli, MD Franck Verschuren, MD Albert Trinh-Duc, MD Pierre-Marie Roy, MD Jeannot Schmidt, MD Thierry Fumeaux, MD Guy Meyer, MD Daniel Hayoz, MD Pierre-Nicolas Carron, MD Pierre-Yves Salaun, MD François Sarasin, MD Olivier Rutschmann, MD Grégoire Le Gal, MD Marc RighiniMD Helia Robert-EbadiHelia Robert-Ebadi Helia Robert-Ebadi, MD, Division of Angiology and Hemostasis, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, 4, Rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland. Email E-mail Address: [email protected] https://orcid.org/0000-0003-3801-1269 Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, Switzerland (H.R.-E., M.R.). , Philippe RobinPhilippe Robin Service de Médecine Nucléaire, EA 3878 (GETBO), Centre Hospitalier Régional et Universitaire de Brest, Université de Bretagne Occidentale, France (P.R., P.-Y.S.). , Olivier HugliOlivier Hugli Emergency Department, Lausanne University Hospital and University of Lausanne, Switzerland (O.H., P.-N.C.). , Franck VerschurenFranck Verschuren Department of Acute Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Institute of Experimental and Clinical Research, Brussels, Belgium (F.V.). , Albert Trinh-DucAlbert Trinh-Duc https://orcid.org/0000-0002-7931-7996 Centre Hospitalier d'Agen, France (A.T.-D.). , Pierre-Marie RoyPierre-Marie Roy https://orcid.org/0000-0003-4811-6793 Emergency Department, Centre Hospitalier Universitaire d'Angers, Institut MIOVASC, UMR (CNRS 6015–INSERM 1083), Université d'Angers, France (P.-M.R.). , Jeannot SchmidtJeannot Schmidt Centre Hospitalier Universitaire de Clermont- Ferrand, France (J.S.). , Thierry FumeauxThierry Fumeaux https://orcid.org/0000-0002-7427-6902 Hôpital de Nyon, Groupe Hospitalier de l'Ouest Lémanique, Nyon, Switzerland (T.F.). , Guy MeyerGuy Meyer Hôpital Européen Georges Pompidou, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR S 970, France (G.M.). , Daniel HayozDaniel Hayoz Hôpital Cantonal de Fribourg, Switzerland (D.H.). , Pierre-Nicolas CarronPierre-Nicolas Carron Emergency Department, Lausanne University Hospital and University of Lausanne, Switzerland (O.H., P.-N.C.). , Pierre-Yves SalaunPierre-Yves Salaun Service de Médecine Nucléaire, EA 3878 (GETBO), Centre Hospitalier Régional et Universitaire de Brest, Université de Bretagne Occidentale, France (P.R., P.-Y.S.). , François SarasinFrançois Sarasin Emergency Department, Geneva University Hospitals, Switzerland (F.S., O.R.). , Olivier RutschmannOlivier Rutschmann Emergency Department, Geneva University Hospitals, Switzerland (F.S., O.R.). , Grégoire Le GalGrégoire Le Gal Ottawa Health Research Institute, ON, Canada (G.L.G.). , Marc RighiniMarc Righini Division of Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, Switzerland (H.R.-E., M.R.). Originally published3 May 2021https://doi.org/10.1161/CIRCULATIONAHA.120.052780Circulation. 2021;143:1828–1830Diagnosis of pulmonary embolism (PE) relies on the sequential use of pretest probability (PTP), plasma D-dimer, and computed tomography pulmonary angiography.1,2 D-dimer <500 µg/L safely excludes PE in association with a low or intermediate (nonhigh) PTP in approximately one-third of outpatients. To increase the clinical usefulness of D-dimer, a cutoff adjusted to patient's age was explored. This age-adjusted D-dimer (AADD) cutoff consists of a cutoff <500 µg/L up to 50 years of age and a cutoff <(age × 10) µg/L in patients >50 years of age. After retrospective validation,3 a large prospective multinational management outcome study proved the safety of the AADD cutoff.4 However, the additional validation step needed was the impact analysis of its use in everyday clinical practice.We therefore designed a multinational, prospective, real-life diagnostic outcome study involving 10 hospitals in Belgium, France, and Switzerland. The ethics committees of all participating institutions approved the study, which was registered on ClinicalTrials.gov (NCT 02601846). Patients provided informed consent. The data supporting the findings of this study are available from the corresponding author.Outpatients in whom PE was considered to be ruled out on the basis of a nonhigh PTP and a negative ELISA D-dimer using the AADD cutoff were included and followed up for 3 months. PTP was assessed by the simplified Geneva score, and the AADD cutoff was applied in routine clinical practice to define negative D-dimer.The main outcome was the rate of symptomatic VTE events during follow-up.4 All suspected VTE events and deaths were adjudicated by 3 independent experts blinded to D-dimer levels. Adjudicated VTE events needed to meet objective diagnostic criteria as currently accepted in diagnostic VTE studies.4 The secondary outcome was the proportion of patients with D-dimer between 500 μg/L and the AADD cutoff, that is, the additional diagnostic yield of the AADD cutoff compared with the standard cutoff, in the whole cohort and in patients ≥75 years of age.Between May 2015 and March 2019, 2148 patients were screened, of whom 641 were excluded. Of the 1507 included patients, 1206 had D-dimer levels <500 µg/L and 301 had a D-dimer ≥500 µg/L but below their AADD cutoff (Figure). Twenty patients were lost to follow-up at 3 months, and 57 received anticoagulants for an indication other than a VTE event during follow-up.Download figureDownload PowerPointFigure. RELAX-PE (Age-Adjusted D-Dimer Cutoff to Rule Out Pulmonary Embolism in the Emergency Department: A Real Life Impact Study) study flowchart.DD indicates D-dimer; DVT, deep vein thrombosis; PE, pulmonary embolism; and VTE, venous thromboembolism.Among the remaining 1430 patients, there were 9 deaths attributed to a cause other than PE. Of the 1421 patients with a nonhigh PTP and negative D-dimer using the AADD cutoff left untreated, 20 had suspected VTE. Objective testing excluded VTE in 19 and confirmed nonfatal PE in 1. The overall 3-month VTE risk was therefore very low at 1 in 1421 (0.07% [95% CI, 0.01–0.40]). The 3-month VTE risk in patients with a D-dimer ≥500 µg/L but below their AADD cutoff was 0 in 269 (0.00% [95% CI, 0.00–1.41]).In terms of diagnostic usefulness, using the AADD cutoff resulted in a 20.0% increase in the proportion of negative D-dimer tests in the whole cohort. Among the 226 patients ≥75 years of age, the increase was 67%; only 75 had a D-dimer <500 µg/L, and 151 had a D-dimer between 500 µg/L and their AADD cutoff.Regarding the 20 patients (1.3%) lost to follow-up, 18 of 20 (90%) were in the group of patients with D-dimer $80 million/y.5In terms of prospective data in patients with D-dimer ≥500 µg/L but below their AADD cutoff, the RELAX-PE (Age-Adjusted D-Dimer Cutoff to Rule Out Pulmonary Embolism in the Emergency Department: A Real Life Impact Study) doubles the number of patients in whom the safety of this strategy is confirmed. Indeed, combining the results of the ADJUST-PE and RELAX-PE studies shows a 3-month VTE risk of 1 in 600 (0.17% [95% CI, 0.03–0.94]).In conclusion, our study demonstrates in a prospective real-life setting the safety and increased diagnostic yield of the AADD cutoff. The AADD cutoff is now the most widely validated D-dimer–adjusting strategy to minimize thoracic imaging. With these final validation data, the AADD cutoff can safely be used on a large-scale basis.AcknowledgmentsThe authors thank all physicians from the emergency and vascular medicine departments of participating centers, as well as study nurses, secretaries, and clinical research technicians, for their invaluable help; Khaled Mostaguir and the Geneva University Hospitals Clinical Research Center; the Direction de la Recherche Clinique et de l'Innovation in CHU Brest; the InnoVTE network; and the patients who made the study possible by accepting to participate. They also express their gratitude to the adjudication committee for their important contribution: François Becker, MD; Marc Carrier, MD, MSc; and Philippe Girard, MD. This work is dedicated to the memory of Professor Guy Meyer.The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.This work was presented as an oral communication on August 31, 2020, in the Latest Findings in Pulmonary Circulation, Pulmonary Embolism, Right Heart Failure session at the European Society of Cardiology Annual Congress 2020.Sources of FundingThis work was supported by a grant from the Swiss National Research Foundation (grant 32003B_130863) and a research prize from the Union of Vascular Societies of Switzerland to Dr Robert-Ebadi.DisclosuresNone.FootnotesRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601846.https://www.ahajournals.org/journal/circHelia Robert-Ebadi, MD, Division of Angiology and Hemostasis, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, 4, Rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland. Email helia.[email protected]chReferences1. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jiménez D, et al.; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).Eur Heart J. 2020; 41:543–603. doi: 10.1093/eurheartj/ehz405CrossrefMedlineGoogle Scholar2. Lim W, Le Gal G, Bates SM, Righini M, Haramati LB, Lang E, Kline JA, Chasteen S, Snyder M, Patel P, et al.. American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism.Blood Adv. 2018; 2:3226–3256. doi: 10.1182/bloodadvances.2018024828CrossrefMedlineGoogle Scholar3. Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A, Kruip MJ, Bounameaux H, Büller HR, Roy PM. 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Age-adjusted D-dimer cutoff for the diagnosis of pulmonary embolism: a cost-effectiveness analysis.J Thromb Haemost. 2020; 18:865–875. doi: 10.1111/jth.14733CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails May 4, 2021Vol 143, Issue 18Article InformationMetrics Download: 1,608 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.052780PMID: 33939529 Originally publishedMay 3, 2021 Keywordsfibrin fragment Dpulmonary embolismdiagnosisPDF download SubjectsDiagnostic TestingEmbolismThrombosis
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