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

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

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

Figure 1

Associations of NT-proBNP and HDL-C concentrations with first-onset coronary heart disease, stroke, and heart failure Risk ratios adjusted for age, smoking status, history of diabetes, systolic blood pressure, and total cholesterol and HDL-C concentration (HDL-C concentration only for NT-proBNP concentration analysis) and stratified by sex. Analyses involved 4716 coronary heart disease outcomes (from 34 cohorts), 3768 stroke outcomes (from 30 cohorts), and 2021 heart failure outcomes (from 16 cohorts). The size of the circles is proportional to the inverse of the variance of the respective estimate. Error bars are 95% CIs, estimated from floated variances. HDL-C=HDL cholesterol. NT-proBNP=N-terminal-pro-B-type natriuretic peptide.

Figure 2

Associations of NT-proBNP and HDL-C concentrations with several incident first-onset cardiovascular outcomes Risk ratios adjusted for age, smoking status, history of diabetes, systolic blood pressure, and total cholesterol and HDL-C concentration (HDL-C concentration only for NT-proBNP concentration analysis) and stratified by sex. HDL-C=HDL cholesterol. NT-proBNP=N-terminal-pro-B-type natriuretic peptide. *Top versus bottom third of NT-proBNP concentration. †Bottom versus top third of HDL-C concentration. ‡Subsumes deaths due to cardiac arrhythmia, hypertensive disease, pulmonary embolism, complications and ill defined descriptions of heart disease, sudden death, aortic aneurysms, and peripheral vascular disease.

Figure 3

Improvement in risk discrimination for first-onset individual and composite cardiovascular disease outcomes by addition of information about NT-proBNP concentration compared with that about HDL-C concentration Analyses involved 8323 outcomes for the combination of coronary heart disease plus stroke (from 32 cohorts), 6582 outcomes for the combination of coronary heart disease plus stroke plus heart failure (from 22 cohorts), 4552 coronary heart disease outcomes (from 32 cohorts), 3768 stroke outcomes (from 30 cohorts), and 2021 heart failure outcomes (from 16 cohorts). HDL-C=HDL cholesterol. NT-proBNP=N-terminal-pro-B-type natriuretic peptide. *The reference model included information about age, sex, smoking, systolic blood pressure, history of diabetes, and concentration of total cholesterol.

Figure 4

Improvement in risk discrimination for first-onset individual and composite cardiovascular outcomes by addition of information about CRP and NT-proBNP concentration to a model with conventional risk factors Analyses involved 7618 outcomes for the combination of coronary heart disease plus stroke (from 28 cohorts), 5492 outcomes for the combination of coronary heart disease plus stroke plus heart failure (from 18 cohorts), 4120 coronary heart disease outcomes (from 27 cohorts), 3487 stroke outcomes (from 26 cohorts), and 1606 heart failure outcomes (from 13 cohorts). CRP=C-reactive protein. NT-proBNP=N-terminal-pro-B-type natriuretic peptide. *The reference model included information about age, sex, smoking, systolic blood pressure, history of diabetes, and concentrations of total and HDL cholesterol.