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      Development and validation of a decision support tool for the diagnosis of acute heart failure: systematic review, meta-analysis, and modelling study

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      1 , * , 1 , 2 , * , 1 , * , 1 , 3 , 4 , 5 , 6 , 5 , 7 , 5 , 5 , 8 , 9 , 10 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 27 , 28 , 29 , 30 , 30 , 31 , 1 , 1 , 2 , 1 , 32 , 22 , 33 , 34 , 5 , 14 , 15 , 1 , 2 , CoDE-HF investigators, , , , , , , , , , , , , , , ,
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          Abstract

          Objectives

          To evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with clinical characteristics.

          Design

          Individual patient level data meta-analysis and modelling study.

          Setting

          Fourteen studies from 13 countries, including randomised controlled trials and prospective observational studies.

          Participants

          Individual patient level data for 10 369 patients with suspected acute heart failure were pooled for the meta-analysis to evaluate NT-proBNP thresholds. A decision support tool (Collaboration for the Diagnosis and Evaluation of Heart Failure (CoDE-HF)) that combines NT-proBNP with clinical variables to report the probability of acute heart failure for an individual patient was developed and validated.

          Main outcome measure

          Adjudicated diagnosis of acute heart failure.

          Results

          Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure (73.3% (2286/3119) and 29.0% (1802/6208) in those with and without previous heart failure, respectively). The negative predictive value of the guideline recommended rule-out threshold of 300 pg/mL was 94.6% (95% confidence interval 91.9% to 96.4%); despite use of age specific rule-in thresholds, the positive predictive value varied at 61.0% (55.3% to 66.4%), 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), in patients aged <50 years, 50-75 years, and >75 years, respectively. Performance varied in most subgroups, particularly patients with obesity, renal impairment, or previous heart failure. CoDE-HF was well calibrated, with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively). In patients without previous heart failure, the diagnostic performance was consistent across all subgroups, with 40.3% (2502/6208) identified at low probability (negative predictive value of 98.6%, 97.8% to 99.1%) and 28.0% (1737/6208) at high probability (positive predictive value of 75.0%, 65.7% to 82.5%) of having acute heart failure.

          Conclusions

          In an international, collaborative evaluation of the diagnostic performance of NT-proBNP, guideline recommended thresholds to diagnose acute heart failure varied substantially in important patient subgroups. The CoDE-HF decision support tool incorporating NT-proBNP as a continuous measure and other clinical variables provides a more consistent, accurate, and individualised approach.

          Study registration

          PROSPERO CRD42019159407.

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          Most cited references46

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          Meta-analysis in clinical trials

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            QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.

            In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.
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                Author and article information

                Contributors
                Role: cardiology specialist registrar and clinical lecturer
                Role: postdoctoral researcher
                Role: cardiology specialist registrar
                Role: foundation year doctor
                Role: biochemist
                Role: professor
                Role: medical doctor
                Role: cardiology fellow
                Role: statistician
                Role: cardiologist
                Role: vice chairman of academic affairs
                Role: associate professor
                Role: cardiologist
                Role: research manager
                Role: professor
                Role: cardiologist
                Role: professor
                Role: associate professor
                Role: statistician
                Role: professor
                Role: internist
                Role: internist
                Role: cardiologist
                Role: cardiologist
                Role: professor
                Role: emergency physician
                Role: cardiologist
                Role: laboratory physician
                Role: professor
                Role: professor
                Role: professor
                Role: associate professor
                Role: professor
                Role: emergency physician
                Role: emergency physician
                Role: associate professor
                Role: professor
                Role: consultant cardiologist
                Role: associate professor
                Role: associate professor
                Role: professor
                Role: professor
                Role: professor
                Role: professor
                Role: professor
                Journal
                BMJ
                BMJ
                BMJ-UK
                bmj
                The BMJ
                BMJ Publishing Group Ltd.
                0959-8138
                1756-1833
                2022
                13 June 2022
                : 377
                : e068424
                Affiliations
                [1 ]British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
                [2 ]Usher Institute, University of Edinburgh, Edinburgh, UK
                [3 ]Department of Biochemistry, Cochin Hospital, Assistance Publique-Hopitaux de Paris, Paris, France
                [4 ]Department of Emergency Medicine, Princess Grace Hospital Center, Monaco, Principality of Monaco
                [5 ]Cardiovascular Research Institute of Basel, Department of Cardiology, University Hospital Basel, Basel, Switzerland
                [6 ]Department of Internal Medicine, University Hospital Basel, University of Basel, Switzerland
                [7 ]Liverpool Heart and Chest Hospital, Liverpool, UK
                [8 ]Inova Heart and Vascular Institute, Falls Church, VA, USA
                [9 ]Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD, USA
                [10 ]University of Toronto, St Michael’s Hospital, Toronto, ON, Canada
                [11 ]Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, CIBERCV, Spain
                [12 ]Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
                [13 ]University of Amsterdam, Amsterdam, Netherlands
                [14 ]Harvard Medical School, Boston, MA, USA
                [15 ]Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA
                [16 ]BRAHMS, Thermo Fisher Scientific, Hennigsdorf, Germany
                [17 ]Department of Emergency and Acute Medicine with Chest Pain Units, Charité – Universitätsmedizin Berlin, Campus Mitte and Virchow, Berlin, Germany
                [18 ]Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
                [19 ]Department of Internal Medicine, Division of Pharmacology and Vascular Medicine, Erasmus Medical Center, Rotterdam, Netherlands
                [20 ]Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
                [21 ]Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
                [22 ]Christchurch Heart Institute, University of Otago, Christchurch, New Zealand
                [23 ]Emergency Medicine Department, National University Hospital, Singapore
                [24 ]Department of Internal Medicine, Krankenhaus Bad Ischl, Bad Ischl, Austria
                [25 ]Department of Laboratory Medicine, Hospital Voecklabruck, Voecklabruck, Austria
                [26 ]Institute for Clinical Chemistry, University Medical Centre Mannheim, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany
                [27 ]First Department of Medicine, University Medical Centre Mannheim, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany
                [28 ]University of Milan Bicocca, ASST-Brianza, Pio XI Hospital of Desio, Internal Medicine, Desio, Italy
                [29 ]Clinica Medica, University Milan Bicocca, Milan, Italy
                [30 ]Department of Emergency Medicine, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
                [31 ]Department of Internal Medicine III, Division of Cardiology, University Hospital of Heidelberg, Ruprecht‐Karls University Heidelberg, Heidelberg, Germany
                [32 ]London School of Hygiene and Tropical Medicine, London, UK
                [33 ]Cardiovascular Research Institute, National University Heart Centre Singapore, Singapore
                [34 ]British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
                [* ]Contributed equally
                Author notes
                Correspondence to: N L Mills nick.mills@ 123456ed.ac.uk (or @HighSTEACS on Twitter)
                Author information
                https://orcid.org/0000-0003-0533-7991
                Article
                bmj-2021-068424.R2 leek068424
                10.1136/bmj-2021-068424
                9189738
                35697365
                5ca7df0a-4453-4d23-8797-2ccafdb20a6e
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 April 2012
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000589, Chief Scientist Office;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000274, British Heart Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Categories
                Research

                Medicine
                Medicine

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