Predictors of Elevated NT-proBNP Levels in a High-Risk Outpatient Population for Heart Failure: Determination Using Clinical Decision Limit, Reference Intervals, and Age- and Sex-Adjusted NT-proBNP Ratio Methods

Aim        To identify predictors of increased N-terminal pro-brain natriuretic peptide (NT-proBNP) in a population of outpatients at a high risk for chronic heart failure (CHF) using methods based on the clinical decision limit (CDL), reference intervals (RI), and age- and sex-adjusted NT-proBNP ratio.

Material and methods    Timely diagnosis and initiation of treatment at the early stages of CHF improve the prognosis of patients. Accordingly, a program for supporting patients at a high-risk of CHF by measuring NT-proBNP was implemented in all federal districts (FDs) of the Russian Federation. The analysis included 11,740 patients at high risk of developing CHF, who had a single NT-proBNP measurement in an outpatient setting. The inclusion criteria were age >18 years, symptoms and signs of CHF and/or abnormalities on electrocardiogram and/or the presence of diseases (arterial hypertension and/or any form of ischemic heart disease). The analysis included determining the proportion of patients with NT-proBNP test results above the CDL (NT-proBNP ≥125 pg/ml) and above the RI (97.5th percentile). For additional assessment, the age- and gender-adjusted NT-proBNP ratio was used. The risk of elevated NT-proBNP was assessed based on CDL, RI, and the NT-proBNP ratio.

Results  The median age of patients was 66 [58.0; 73.0] years, 55.8% were >65 years, and 59.3% were women. In 43.5% of patients, the NT-proBNP concentration was less than 125 pg/ml. The risk of achieving CDL was 50% higher among men, associated with the patient's age, and increased by 73% in the 45-54 age group, 2.52 times in the 55-64 age group, and 6.62 times in the >65 years age group compared to the 18-44 age group. Living in a city with a population of less than one million people increased the risk of achieving CDL by 17% compared to living in a city with a population of over a million. NT-proBNP values above the RI were achieved by 22% of patients, with the risk being 69% higher among men and 24% higher among patients living in cities with a population of less than one million. Evaluation of the NT-proBNP test results using the RI criterion showed that 44.3% of patients with normal RI values had NT-proBNP values above the CDL (≥125 pg/ml). The NT-proBNP ratio was the lowest in the Ural Federal District and the highest in the Far Eastern Federal District. The risk of an increased NT-proBNP ratio ≥1 was higher among men by 67% (p<0.001), for residents of small towns by 21% (p<0.001), and for residents of the Far Eastern Federal District compared to any other region (p<0.001).

Conclusion         Independent risk factors for elevated NT-proBNP when assessed by the RI and NT-proBNP ratio included male gender, residence in cities with a population of less than one million, and residence in the Far Eastern Federal District. Assessing the NT-proBNP test solely based on the CDL, without taking into account physiological changes related to gender and age, carries a risk of overdiagnosis of CHF.

1. Polyakov D.S., Fomin I.V., Belenkov Yu.N., Mareev V.Yu., Ageev F.T., Artemjeva E.G. et al. Chronic heart failure in the Russian Federation: what has changed over 20 years of follow-up? Results of the EPOCH-CHF study. Kardiologiia. 2021;61(4):4–14. DOI: 10.18087/cardio.2021.4.n1628

2. Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, Pedro Ferreira J, Zannad F et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. The Lancet. 2020;396(10244):121–8. DOI: 10.1016/S0140-6736(20)30748-0

3. Shlyakhto E.V., Belenkov Yu.N., Boytsov S.A., Villevalde S.V., Galyavich A.S., Glezer M.G. et al. Interim analysis of a prospective observational multicenter registry study of patients with chronic heart failure in the Russian Federation ‘PRIORITET-CHF’: initial characteristics and treatment of the first included patients. Russian Journal of Cardiology. 2023;28(10):93–103. DOI: 10.15829/1560-4071-2023-5593

4. Crespo-Leiro MG, Barge-Caballero E. Advanced Heart Failure: Definition, Epidemiology, and Clinical Course. Heart Failure Clinics. 2021;17(4):533–45. DOI: 10.1016/j.hfc.2021.06.002

5. Bozkurt B, Coats AJ, Tsutsui H, Abdelhamid M, Adamopoulos S, Albert N et al. Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. Journal of Cardiac Failure. 2021;27(4):387–413. DOI: 10.1016/j.cardfail.2021.01.022

6. Bayes‐Genis A, Docherty KF, Petrie MC, Januzzi JL, Mueller C, Anderson L et al. Practical algorithms for early diagnosis of heart failure and heart stress using NT‐proBNP: A clinical consensus statement from the Heart Failure Association of the ESC. European Journal of Heart Failure. 2023;25(11):1891–8. DOI: 10.1002/ejhf.3036

7. Talha KM, Januzzi JL, Meng T, Greene SJ, Vaduganathan M, Janicijevic TK et al. Use of natriuretic peptides and echocardiography for diagnosing heart failure. European Journal of Heart Failure. 2024;26(3):551–60. DOI: 10.1002/ejhf.3165

8. Shalnova S.A., Kutsenko V.A., Yakushin S.S., Kapustina A.V., Evstifeeva S.E., Balanova Yu.A. et al. Associations of elevated levels of brain natriuretic peptide and heart failure and their contribution to survival in the Russian middle-aged population: data from the ESSERF study. Cardiovascular Therapy and Prevention. 2023;22(6):6–13. DOI: 10.15829/1728-8800-2023-3553

9. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. 2021;42(36):3599–726. DOI: 10.1093/eurheartj/ehab368

10. Galyavich A.S., Tereshchenko S.N., Uskach T.M., Ageev F.T., Aronov D.M., Arutyunov G.P. et al. 2024 Clinical practice guidelines for Chronic heart failure. Russian Journal of Cardiology. 2024;29(11):251–349. DOI: 10.15829/1560-4071-2024-6162

11. Prausmüller S, Resl M, Arfsten H, Spinka G, Wurm R, Neuhold S et al. Performance of the recommended ESC/EASD cardiovascular risk stratification model in comparison to SCORE and NT-proBNP as a single biomarker for risk prediction in type 2 diabetes mellitus. Cardiovascular Diabetology. 2021;20(1):34. DOI: 10.1186/s12933-021-01221-w

12. BNP, NT-proBNP, and MR-proANP Assays: Analytical Characteristics Designated by Manufacturer IFCC Committee on Clinical Applications of Cardiac Bio-Markers (C-CB) v062024. Av. at: https://pub180a8d00f517477ba49634e6b2b147e3.r2.dev/2024/03/BNP-NTproBNP-and-MR-proANP-Assays-Analytical-Characteristics-Designated-By-Manufacturer-v062024.pdf.

13. Vinogradova N.G., Berestovskaya V.S., Blankova Z.N., Vavilova T.V., Gomyranova N.V., Masenko V.P. et al. Laboratory Aspects of Using the Results of NT-Probnp Concentration Immunochemical Determination in the Management of Patients With Heart Failure: Support For Clinical Decision-Making. Kardiologiia. 2024;64(8):68–78. DOI: 10.18087/cardio.2024.8.n2720

14. Mu S, Echouffo-Tcheugui JB, Ndumele CE, Coresh J, Juraschek S, Brady T et al. NT-proBNP Reference Intervals in Healthy U.S. Children, Adolescents, and Adults. The Journal of Applied Laboratory Medicine. 2023;8(4):700–12. DOI: 10.1093/jalm/jfad024

15. Ezekowitz JA, Alemayehu W, Rathwell S, Grant AD, Fiuzat M, Whellan DJ et al. The influence of comorbidities on achieving an N‐terminal pro‐b‐type natriuretic peptide target: a secondary analysis of the GUIDE‐IT trial. ESC Heart Failure. 2022;9(1):77–86. DOI: 10.1002/ehf2.13692

16. Roche Diagnostics GmbH. Instruction for use Elecsys proBNP II. Av. at: https://elabdoc.rochediagnostics.ru/api/documents/download/33d4faf3-b354-ef11-2b91-005056a71a5d.

17. Bernard J, Jean G, Bienjonetti-Boudreau D, Jacques F, Tastet L, Salaun E et al. Prognostic utility of N-terminal pro B-type natriuretic peptide ratio in mixed aortic valve disease. Open Heart. 2023;10(2):e002361. DOI: 10.1136/openhrt-2023-002361

18. Hutt E, Mentias A, Alashi A, Wadhwa R, Fava A, Lever HM et al. Prognostic value of age-sex adjusted NT-proBNP ratio in obstructive hypertrophic cardiomyopathy. Progress in Cardiovascular Diseases. 2022;74:11–8. DOI: 10.1016/j.pcad.2022.08.002

19. Li D, He W, Yu B, Wang DW, Ni L. NT-proBNP ratio is a potential predictor for COVID-19 outcomes in adult Chinese patients: a retrospective study. Scientific Reports. 2024;14(1):5906. DOI: 10.1038/s41598-024-56329-2

20. Russia’s million-plus cities. Av. at: https://www.statdata.ru/gorodamillionniki-rossii-po-naseleniu.

21. Nogi K, Yamamoto R, Ueda T, Nogi M, Ishihara S, Nakada Y et al. Derivation and validation of a clinical predictive model of NT-proBNP ≥125 pg/mL to detect pre-heart failure. Journal of Cardiology. 2023;82(6):481–9. DOI: 10.1016/j.jjcc.2023.05.011

22. Alehagen U, Goetze JP, Dahlström U. Reference intervals and decision limits for B-type natriuretic peptide (BNP) and its precursor (NTproBNP) in the elderly. Clinica Chimica Acta. 2007;382(1–2):8–14. DOI: 10.1016/j.cca.2007.03.005

23. Averina M, Stylidis M, Brox J, Schirmer H. NT‐ProBNP and high‐sensitivity troponin T as screening tests for subclinical chronic heart failure in a general population. ESC Heart Failure. 2022;9(3):1954–62. DOI: 10.1002/ehf2.13906

24. Singh S, Pandey A, Neeland IJ. Diagnostic and prognostic considerations for use of natriuretic peptides in obese patients with heart failure. Progress in Cardiovascular Diseases. 2020;63(5):649–55. DOI: 10.1016/j.pcad.2020.09.006

25. Bayés-Genis A, Taylor CJ. Elevated NT-proBNP in Heart Failure and CKD: A Genuine Red Flag for Worse Prognosis-Not a False Positive. JACC: Heart Failure. 2025;13(1):40–2. DOI: 10.1016/j.jchf.2024.10.012