Joan Walter, MD, PhD; Jeanne du Fay de Lavallaz, MD, PhD; Luca Koechlin, MD; Tobias Zimmermann, MD; Jasper Boeddinghaus, MD; Ursina Honegger, MSc; Ivo Strebel, MSc; Raphael Twerenbold, MD; Melissa Amrein, MSc; Thomas Nestelberger, MD; Desiree Wussler, MD; Christian Puelacher, MD, PhD; Patrick Badertscher, MD; Michael Zellweger, MD; Gregor Fahrni, MD; Raban Jeger, MD; Christoph Kaiser, MD; Tobias Reichlin, MD; Christian Mueller, MD
Acknowledgment: The authors thank the patients for participating in the study, the staff of the Department of Radiology and Nuclear Medicine of the University Hospital Basel, and the laboratory technicians (particularly Michael Freese, Kathrin Meissner, and Irina Klimmeck) for their most valuable efforts.
Grant Support: By research grants from the European Union, the Swiss National Science Foundation, the Kommission für Technologie und Innovation (Innosuisse, grant 16309.1), the Swiss Heart Foundation (grant FF18111), the Cardiovascular Research Foundation Basel, the University of Basel, the University Hospital Basel, Abbott, Roche, Schiller, and Singulex.
Disclosures: Dr. Walter reports grants from the Swiss Academy of Medical Sciences and the Swiss Heart Foundation during the conduct of the study. Dr. Boeddinghaus reports personal fees from Siemens, Roche Diagnostics, and Ortho Clinical Diagnostics and grants from the University of Basel and the Gottfried and Julia Bangerter-Rhyner Foundation outside the submitted work. Dr. Twerenbold reports grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the Swiss Society of Cardiology, and Cardiovascular Research Foundation Basel and personal fees from Abbott Diagnostics, Amgen, Roche Diagnostics, Siemens, Singulex, BRAHMS, and AstraZeneca outside the submitted work. Dr. Nestelberger reports personal fees from Beckman Coulter, Ortho Clinical Diagnostics, and Orion Pharma outside the submitted work. Dr. Puelacher reports grants from Roche Diagnostics outside the submitted work. Dr. Zellweger reports participation on the Advisory Board of Exploris in Switzerland; however, there is no conflict of interest. Dr. Reichlin reports grants and personal fees from Biosense Webster and Medtronic; grants from Boston Scientific, Biotronik, and Abbott/SJM; and personal fees from Daiichi, BMS-Pfizer, and Bayer outside the submitted work. Dr. Mueller reports grants, personal fees, and nonfinancial support from Roche Diagnostics, Singulex, and BRAHMS; personal fees from Novartis, Amgen, and Sanofi; and grants and nonfinancial support from Abbott outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0080.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement:Study protocol and statistical code: Available from Dr. Walter (e-mail, firstname.lastname@example.org). Data set: Not available.
Corresponding Author: Christian Mueller, MD, CRIB and Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail, email@example.com.
Current Author Addresses: Drs. Walter, du Fay de Lavallaz, Koechlin, Zimmermann, Boeddinghaus, Twerenbold, Nestelberger, Wussler, Puelacher, Badertscher, Zellweger, Fahrni, Jeger, Kaiser, and Mueller; Ms. Honegger; Mr. Strebel; and Ms. Amrein: Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
Dr. Reichlin: Department of Cardiology, University Hospital Bern, CH-3010 Bern, Switzerland.
Author Contributions: Conception and design: J. Walter, U. Honegger, M. Zellweger, C. Mueller.
Analysis and interpretation of the data: J. Walter, J. du Fay de Lavallaz, U. Honegger, M. Zellweger, T. Reichlin, C. Mueller.
Drafting of the article: J. Walter, T. Nestelberger, C. Mueller.
Critical revision of the article for important intellectual content: J. Walter, J. du Fay de Lavallaz, L. Koechlin, T. Zimmermann, J. Boeddinghaus, U. Honegger, R. Twerenbold, D. Wussler, C. Puelacher, P. Badertscher, M. Zellweger, G. Fahrni, R. Jeger, C. Kaiser, T. Reichlin, C. Mueller.
Final approval of the article: J. Walter, J. du Fay de Lavallaz, L. Koechlin, T. Zimmermann, J. Boeddinghaus, U. Honegger, I. Strebel, R. Twerenbold, M. Amrein, T. Nestelberger, D. Wussler, C. Puelacher, P. Badertscher, M. Zellweger, G. Fahrni, R. Jeger, C. Kaiser, T. Reichlin, C. Mueller.
Provision of study materials or patients: U. Honegger, R. Jeger, C. Mueller.
Statistical expertise: J. du Fay de Lavallaz, T. Zimmermann, T. Reichlin, C. Mueller.
Obtaining of funding: R. Twerenbold, T. Reichlin, C. Mueller.
Administrative, technical, or logistic support: L. Koechlin, I. Strebel, R. Twerenbold, T. Reichlin, C. Mueller.
Collection and assembly of data: J. Walter, J. du Fay de Lavallaz, U. Honegger, I. Strebel, R. Twerenbold, M. Amrein, C. Puelacher, P. Badertscher, G. Fahrni, R. Jeger, T. Reichlin.
The optimal noninvasive method for surveillance in symptomatic patients with stable coronary artery disease (CAD) is unknown.
To apply a novel approach using very low concentrations of high-sensitivity cardiac troponin I (hs-cTnI) for exclusion of inducible myocardial ischemia in symptomatic patients with CAD.
Prospective diagnostic cohort study. (ClinicalTrials.gov: NCT01838148)
1896 consecutive patients with CAD referred with symptoms possibly related to inducible myocardial ischemia.
Presence of inducible myocardial ischemia was adjudicated using myocardial perfusion imaging with single-photon emission computed tomography, as well as coronary angiography and fractional flow reserve measurements where available. Staff blinded to adjudication measured circulating hs-cTn concentrations. An hs-cTnI cutoff of 2.5 ng/L, derived previously in mostly asymptomatic patients with CAD, was assessed. Predefined target performance criteria were at least 90% negative predictive value (NPV) and at least 90% sensitivity for exclusion of inducible myocardial ischemia. Sensitivity analyses were based on measurements with an hs-cTnT assay and an alternative hs-cTnI assay with even higher analytic sensitivity (limit of detection, 0.1 ng/L).
Overall, 865 patients (46%) had inducible myocardial ischemia. The hs-cTnI cutoff of 2.5 ng/L provided an NPV of 70% (95% CI, 64% to 75%) and a sensitivity of 90% (CI, 88% to 92%) for exclusion of inducible myocardial ischemia. No hs-cTnI cutoff reached both performance characteristics predefined as targets. Similarly, using the alternative assays for hs-cTnI or hs-cTnT, no cutoff achieved the target performance: hs-cTnT concentrations less than 5 ng/L yielded an NPV of 66% (CI, 59% to 72%), and hs-cTnI concentrations less than 2 ng/L yielded an NPV of 68% (CI, 62% to 74%).
Data were generated in a large single-center diagnostic study using central adjudication.
In symptomatic patients with CAD, very low hs-cTn concentrations, including hs-cTnI concentrations less than 2.5 ng/L, do not generally allow users to safely exclude inducible myocardial ischemia.
European Union, Swiss National Science Foundation, Kommission für Technologie und Innovation (Innosuisse), Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University of Basel, University Hospital Basel, Roche, Abbott, and Singulex.
Walter J, du Fay de Lavallaz J, Koechlin L, et al. Using High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia in Symptomatic Patients: A Cohort Study. Ann Intern Med. 2020;172:175–185. [Epub ahead of print 7 January 2020]. doi: https://doi.org/10.7326/M19-0080
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Published: Ann Intern Med. 2020;172(3):175-185.
Published at www.annals.org on 7 January 2020
Cardiac Diagnosis and Imaging, Cardiology, Coronary Heart Disease, Hospital Medicine.
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