Author + information
- Received November 17, 2017
- Revision received December 28, 2017
- Accepted December 29, 2017
- Published online February 7, 2018.
- Gianluigi Savarese, MDa,∗ (, )
- Nicola Orsini, PhDb,
- Camilla Hage, PhDa,
- Ola Vedin, MD, PhDc,
- Francesco Cosentino, MD, PhDa,d,
- Giuseppe M.C. Rosano, MD, PhDe,f,
- Ulf Dahlström, MD, PhDg,h and
- Lars H. Lund, MD, PhDa,d
- aDivision of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- bDepartment of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden
- cDepartment of Medical Sciences, Uppsala University and Uppsala Clinical Research Center, Uppsala, Sweden
- dHeart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
- eCardiovascular and Cell Sciences Research Institute, St. George's University, London, United Kingdom
- fIstituti di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy
- gDepartment of Cardiology, Linköping University, Linköping, Sweden
- hDepartment of Medical and Health Sciences, Linköping University, Linköping, Sweden
- ↵∗Address for correspondence:
Dr. Gianluigi Savarese, Department of Medicine, Cardiology Unit, Karolinska Institutet, S1:02, 171 76, Stockholm, Sweden.
Objectives The purpose of this study was to assess the association between N-terminal pro–B-type natriuretic peptide (NT-proBNP) and cardiovascular (CV) versus non-CV events and between NT-proBNP and potential treatment effects in heart failure (HF) with preserved, mid-range, and reduced ejection fraction (HFpEF, HFmrEF, and HFrEF, respectively) and clinically relevant subgroups.
Background Optimizing patient eligibility criteria in HF trials requires biomarkers that enrich for CV but not for non-CV events and select patients most likely to respond to the tested intervention.
Methods In the Swedish HF registry population stratified by EF category, we used Kaplan-Meier curves to estimate unadjusted CV and non-CV risks (mortality or hospitalization); Poisson regressions to calculate crude event rates of CV and non-CV events according to NT-proBNP levels; and Cox regressions to calculate the adjusted hazard ratios for HF therapies according to NT-proBNP ≤ or > median.
Results In a cohort of 15,849 patients (23% HFpEF, 21% HFmrEF, 56% HFrEF), median NT-proBNP was 2,037, 2,192, and 3,141 pg/ml, respectively. With increasing NT-proBNP, CV event rates increased more steeply than non-CV rates (range 20 to 160 and 30 to 100 per 100 patient-years in HFpEF; 20 to 130 and 20 to 100 in HFmrEF; and 20 to 110 and 20 to 50 in HFrEF, respectively). The CV-to-non-CV ratio increased with increasing NT-proBNP in HFpEF and HFrEF, but only in the lower range in HFmrEF. The association between treatments (e.g., angiotensin-converting enzyme-inhibitor, angiotensin II receptor blockers, and beta-blockers) and outcomes was consistent in NT-proBNP ≤ and > median.
Conclusions In HF trial design in different EF categories, NT-proBNP may be a useful tool for eligibility and enrichment for CV events, but its role in predicting a potential treatment response remains unclear.
This study was supported by grants 2013-23897-104604-23 and 523-2014-2336 from the Swedish Research Council; grants 20120321 and 20150557 from the Swedish Heart Lung Foundation; and a grant from Relypsa, Inc. No funding agency had any role in the design and conduct of the study, collection, management, analysis, or interpretation of the data, or in the preparation or approval of the manuscript. Dr. Savarese has received research grants from Merck Sharp & Dohme Italy and the Swedish Heart and Lung Foundation. Dr. Hage has received consulting fees from Novartis; and honoraria from Merck Sharp & Dohme. Dr. Vedin has received consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Fresenius Medicare, and Alnylam Pharmaceuticals. Dr. Cosentino has received research support from the Swedish Research Council, Heart and Lung Foundation, Karolinska Institute, European Foundation for the Study of Diabetes, and the Stiftelsen Frimurare Barnhuset Foundation; and has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Abbott, Bayer, and Novo Nordisk. Dr. Dahlström has received research grants from AstraZeneca; and honoraria from AstraZeneca and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received November 17, 2017.
- Revision received December 28, 2017.
- Accepted December 29, 2017.
- 2018 American College of Cardiology Foundation
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