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      Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis

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          Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.


          In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.


          We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56–1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77–2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010–0·014) and a net reclassification improvement of 0·027 (0·019–0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016–0·022) and a net reclassification improvement of 0·028 (0·019–0·038) for the combination of coronary heart disease, stroke, and heart failure.


          In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.


          British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.

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          Most cited references 38

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          Natriuretic peptides.

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            2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

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              Use of multiple biomarkers to improve the prediction of death from cardiovascular causes.

              The incremental usefulness of adding multiple biomarkers from different disease pathways for predicting the risk of death from cardiovascular causes has not, to our knowledge, been evaluated among the elderly. We used data from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men, to investigate whether a combination of biomarkers that reflect myocardial cell damage, left ventricular dysfunction, renal failure, and inflammation (troponin I, N-terminal pro-brain natriuretic peptide, cystatin C, and C-reactive protein, respectively) improved the risk stratification of a person beyond an assessment that was based on the established risk factors for cardiovascular disease (age, systolic blood pressure, use or nonuse of antihypertensive treatment, total cholesterol, high-density lipoprotein cholesterol, use or nonuse of lipid-lowering treatment, presence or absence of diabetes, smoking status, and body-mass index). During follow-up (median, 10.0 years), 315 of the 1135 participants in our study (mean age, 71 years at baseline) died; 136 deaths were the result of cardiovascular disease. In Cox proportional-hazards models adjusted for established risk factors, all of the biomarkers significantly predicted the risk of death from cardiovascular causes. The C statistic increased significantly when the four biomarkers were incorporated into a model with established risk factors, both in the whole cohort (C statistic with biomarkers vs. without biomarkers, 0.766 vs. 0.664; P<0.001) and in the group of 661 participants who did not have cardiovascular disease at baseline (0.748 vs. 0.688, P=0.03). The improvement in risk assessment remained strong when it was estimated by other statistical measures of model discrimination, calibration, and global fit. Our data suggest that in elderly men with or without prevalent cardiovascular disease, the simultaneous addition of several biomarkers of cardiovascular and renal abnormalities substantially improves the risk stratification for death from cardiovascular causes beyond that of a model that is based only on established risk factors. Copyright 2008 Massachusetts Medical Society.

                Author and article information

                Lancet Diabetes Endocrinol
                Lancet Diabetes Endocrinol
                The Lancet. Diabetes & Endocrinology
                The Lancet, Diabetes & Endocrinology
                1 October 2016
                October 2016
                : 4
                : 10
                : 840-849
                Author notes
                [* ]Correspondence to: Natriuretic Peptides Studies Collaboration, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UKCorrespondence to: Natriuretic Peptides Studies CollaborationDepartment of Public Health and Primary Care, University of CambridgeStrangeways Research LaboratoryCambridgeCB1 8RNUK npsc@

                Writing committee members and collaborators listed at end of paper

                © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license

                This is an open access article under the CC BY license (



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