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Venous Thromboembolism

Effect of a Pulmonary Embolism Diagnostic Strategy on Clinical Outcomes in Patients Hospitalized for COPD ExacerbationA Randomized Clinical Trial

Educational Objective
To understand the benefits and risks of an active strategy for the detection of pulmonary embolism in patients hospitalized for an exacerbation of chronic obstructive pulmonary disease (COPD).

1 Credit CME

JAMA

Published Online: October 5, 2021

Original Investigation

Article Information and Disclosures

David Jiménez, MD, PhD^1,2,3;

Alvar Agustí, MD, PhD⁴;

Eva Tabernero, MD⁵;

Luis Jara-Palomares, MD, PhD⁶;

Ascensión Hernando, MD, PhD⁷;

Pedro Ruiz-Artacho, MD, PhD^3,8;

Gregorio Pérez-Peñate, MD, PhD⁹;

Agustina Rivas-Guerrero, MD¹⁰;

María Jesús Rodríguez-Nieto, MD, PhD^3,11;

Aitor Ballaz, MD¹²;

Ramón Agüero, MD¹³;

Sonia Jiménez, MD¹⁴;

Myriam Calle-Rubio, MD, PhD¹⁵;

Raquel López-Reyes, MD¹⁶;

Pedro Marcos-Rodríguez, MD¹⁷;

Deisy Barrios, MD, PhD¹;

Carmen Rodríguez, MD¹;

Alfonso Muriel, PhD¹⁸;

Laurent Bertoletti, MD, PhD¹⁹;

Francis Couturaud, MD, PhD²⁰;

Menno Huisman, MD, PhD²¹;

José Luis Lobo, MD¹⁰;

Roger D. Yusen, MD²²;

Behnood Bikdeli, MD, MS^23,24,25;

Manuel Monreal, MD, PhD^3,26;

Remedios Otero, MD, PhD^3,6;

for the SLICE Trial Group

Author Affiliations

¹Respiratory Department, Hospital Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, Madrid, Spain
²Medicine Department, Universidad de Alcalá, Madrid, Spain
³CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain
⁴Respiratory Institute, Hospital Clinic, IDIBAPS, Universitat de Barcelona, CIBERES, Barcelona, Spain
⁵Respiratory Department, Hospital Universitario Cruces, Biocruces-Bizkaia, Barakaldo, Spain
⁶Respiratory Department, Virgen del Rocío Hospital and Instituto de Biomedicina, Sevilla
⁷Respiratory Department, Hospital Doce de Octubre, Madrid, Spain
⁸Department of Internal Medicine, Clínica Universidad de Navarra, Madrid; Interdisciplinar Teragnosis and Radiosomics Research Group (INTRA-Madrid), Universidad de Navarra, Madrid, Spain
⁹Respiratory Department and Pulmonary Vascular Unit, HUGC Dr. Negrín, Las Palmas GC, Spain
¹⁰Respiratory Department, Hospital Araba, Vitoria, Spain
¹¹Respiratory Department, Fundación Jiménez Díaz, Madrid, Spain
¹²Respiratory Department, Hospital Galdakao-Usansolo, Bilbao, Spain
¹³Respiratory Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain
¹⁴Emergency Department, Hospital Clinic, IDIBAPS, Barcelona, Spain
¹⁵Respiratory Department, Hospital Clínico San Carlos, Madrid; Medicine Department, Universidad Complutense, Madrid, Spain
¹⁶Respiratory Department, Hospital La Fe, Valencia, Spain
¹⁷Respiratory Department, Complejo Hospitalario Universitario de A Coruña (CHUAC), INIBIC, Universidade da Coruña, A Coruña, Spain
¹⁸Biostatistics Department, Ramón y Cajal Hospital and Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, CIBERESP, Madrid, Spain
¹⁹CHU de St-Etienne, Service de Médecine Vasculaire et Thérapeutique; INSERM, UMR1059, Université Jean-Monnet; INSERM, CIC-1408, CHU de Saint-Etienne; INNOVTE, CHU de Saint-Etienne; all in F-42055, Saint-Etienne, France
²⁰Department of Internal Medicine and Chest Diseases, EA3878 (G.E.T.B.O.), CIC INSERM 0502, University Hospital of Brest, European University of Occidental Brittany, Brest, France
²¹Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
²²Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences, Washington University School of Medicine in St Louis, St Louis, Missouri
²³Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
²⁴Center for Outcomes Research and Evaluation (CORE), Yale University School of Medicine, New Haven, Connecticut
²⁵Cardiovascular Research Foundation, New York, New York
²⁶Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona; Universidad Católica de Murcia, Murcia, Spain

SLICE Trial Groupfor the

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Key Points

Question Does an active search for pulmonary embolism (PE) improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD)?

Findings This multicenter randomized clinical trial included 746 patients who required hospitalization for exacerbation of COPD and were randomized to receive usual care plus an active strategy for diagnosing PE or usual care alone. The primary outcome (a composite of nonfatal symptomatic venous thromboembolism, readmission for COPD, or death within 90 days after randomization) occurred in 29.7% of patients in the intervention group vs 29.2% in the control group, a difference that was not statistically significant.

Meaning Among patients hospitalized for an exacerbation of COPD, addition of an active diagnostic strategy for PE to usual care compared with usual care alone did not improve a composite set of health outcomes.

Abstract

Importance Active search for pulmonary embolism (PE) may improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD).

Objective To compare usual care plus an active strategy for diagnosing PE with usual care alone in patients hospitalized for COPD exacerbation.

Design, Setting, and Participants Randomized clinical trial conducted across 18 hospitals in Spain. A total of 746 patients were randomized from September 2014 to July 2020 (final follow-up was November 2020).

Interventions Usual care plus an active strategy for diagnosing PE (D-dimer testing and, if positive, computed tomography pulmonary angiogram) (n = 370) vs usual care (n = 367).

Main Outcomes and Measures The primary outcome was a composite of nonfatal symptomatic venous thromboembolism (VTE), readmission for COPD, or death within 90 days after randomization. There were 4 secondary outcomes, including nonfatal new or recurrent VTE, readmission for COPD, and death from any cause within 90 days. Adverse events were also collected.

Results Among the 746 patients who were randomized, 737 (98.8%) completed the trial (mean age, 70 years; 195 [26%] women). The primary outcome occurred in 110 patients (29.7%) in the intervention group and 107 patients (29.2%) in the control group (absolute risk difference, 0.5% [95% CI, −6.2% to 7.3%]; relative risk, 1.02 [95% CI, 0.82-1.28]; P = .86). Nonfatal new or recurrent VTE was not significantly different in the 2 groups (0.5% vs 2.5%; risk difference, −2.0% [95% CI, −4.3% to 0.1%]). By day 90, a total of 94 patients (25.4%) in the intervention group and 84 (22.9%) in the control group had been readmitted for exacerbation of COPD (risk difference, 2.5% [95% CI, −3.9% to 8.9%]). Death from any cause occurred in 23 patients (6.2%) in the intervention group and 29 (7.9%) in the control group (risk difference, −1.7% [95% CI, −5.7% to 2.3%]). Major bleeding occurred in 3 patients (0.8%) in the intervention group and 3 patients (0.8%) in the control group (risk difference, 0% [95% CI, −1.9% to 1.8%]; P = .99).

Conclusions and Relevance Among patients hospitalized for an exacerbation of COPD, the addition of an active strategy for the diagnosis of PE to usual care, compared with usual care alone, did not significantly improve a composite health outcome. The study may not have had adequate power to assess individual components of the composite outcome.

Trial Registration ClinicalTrials.gov Identifier: NCT02238639

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Article Information

Corresponding Author: David Jiménez, MD, PhD, Respiratory Department and Medicine Department, Ramón y Cajal Hospital, IRYCIS and Alcalá University, CIBER Enfermedades Respiratorias (CIBERES), Colmenar Rd, Km. 9,100, 28034 Madrid, Spain (djimenez.hrc@gmail.com).

Accepted for Publication: August 16, 2021.

Author Contributions: Dr D. Jiménez had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: D. Jimenez, Calle Rubio, Rodriguez, Bertoletti, Yusen, Monreal, Otero.

Acquisition, analysis, or interpretation of data: D. Jimenez, Agusti, Tabernero, Jara-Palomares, Hernando, Ruiz-Artacho, Perez-Peñate, Rivas-Guerrero, Rodriguez Nieto, Ballaz, Aguero, S. Jimenez, Calle Rubio, Lopez-Reyes, Marcos, Barrios, Muriel, Bertoletti, Couturaud, Huisman, Lobo, Yusen, Bikdeli, Monreal, Otero.

Drafting of the manuscript: D. Jimenez, Agusti, Marcos, Barrios, Rodriguez.

Critical revision of the manuscript for important intellectual content: D. Jimenez, Agusti, Tabernero, Jara-Palomares, Hernando, Ruiz-Artacho, Perez-Peñate, Rivas-Guerrero, Rodriguez Nieto, Ballaz, Aguero, S. Jimenez, Calle Rubio, Lopez-Reyes, Marcos, Muriel, Bertoletti, Couturaud, Huisman, Lobo, Yusen, Bikdeli, Monreal, Otero.

Statistical analysis: D. Jimenez, Marcos, Muriel, Yusen.

Obtained funding: D. Jimenez, Jara-Palomares, Barrios, Otero.

Administrative, technical, or material support: D. Jimenez, Perez-Peñate, Lopez-Reyes, Marcos.

Supervision: D. Jimenez, Agusti, Rivas-Guerrero, Calle Rubio, Marcos, Bertoletti, Huisman, Monreal, Otero.

Conflict of Interest Disclosures: Dr D. Jimenez reported receiving personal fees from Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, and Pfizer and grants from Daiichi Sankyo, Rovi, and Sanofi outside the submitted work. Dr Agusti reported receiving grants and personal fees from AstraZeneca, GlaxoSmithKline, and Menarini and personal fees from Chiesi outside the submitted work. Dr Jara-Palomares reported receiving grants from Leo Pharma and MSD and personal fees from Daichii, Rovi, GlaxoSmithKline, and Actellion outside the submitted work. Dr Ruiz-Artacho reported receiving personal fees from Bristol Myers Squibb, Leo Pharma, and Daiichi Sankyo and grants from ROVI outside the submitted work. Dr Calle Rubio reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Menarini, Novartis, Grifols, and GlaxoSmithKline and consulting fees from GlaxoSmithKline, Gebro Pharma, and Novartis during the conduct of the study. Dr Bertoletti reported receiving personal fees from board, symposia, and congress travel from Actelion, Aspen, Bayer, Bristol Myers Squibb/Pfizer, Leo Pharma, and MSD and travel support from Daiichi Sankyo outside the submitted work. Dr Couturaud reported receiving grants from Bristol Myers Squibb; personal fees from Bayer, AstraZeneca, and Bristol Myers Squibb; and travel support from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, InterMune, and Actelion outside the submitted work. Dr Huisman reported receiving grants from Pfizer-Bristol Myers Squibb Alliance, Bayer Health Care, ZonMw, the Dutch Heart Foundation outside the submitted work. Dr Yusen reported receiving personal fees from Ortho Pharmaceuticals for providing expert review of venous thromboembolism cases and relationship to hormonal contraceptive therapy, Organon for providing expert review of venous thromboembolism cases and relationship to hormonal contraceptive therapy, Merck for providing expert review of venous thromboembolism cases and relationship to hormonal contraceptive therapy, Portola for providing consulting related to the oral anticoagulant betrixaban, and Janssen for providing consulting related to the oral anticoagulant rivaroxaban and grants from Cyclomedica for funding as a co-investigator of a study of an imaging agent, Technegas, outside the submitted work. Dr Bikdeli reported being a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of inferior vena cava filters. Dr Monreal reported receiving educational grants from Sanofi and Rovi Pharmaceuticals for research and personal fees from Sanofi and Leo Pharma for advisory committees outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grants from the Instituto de Salud Carlos III (PI14/00400), Chest Foundation, Sociedad Española de Neumología y Cirugía Torácica (SEPAR), Neumosur, and Daiichi Sankyo.

Role of the Funder/Sponsor: The funder 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.

Group Information: A listing of the SLICE investigators appears in Supplement 4.

Additional Contributions: We express our gratitude to S&H Medical Science Service for their quality control data, logistic, and administrative support.

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 [and Self-Assessment requirements] 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.