Impact of Body Mass Index on the Accuracy of N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide for Predicting Outcomes in Patients With Chronic Heart Failure and Reduced Ejection Fraction: Insights From the PARADIGM-HF Study (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial).

Abstract

HomeCirculationVol. 134, No. 22Impact of Body Mass Index on the Accuracy of N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide for Predicting Outcomes in Patients With Chronic Heart Failure and Reduced Ejection Fraction Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBImpact of Body Mass Index on the Accuracy of N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide for Predicting Outcomes in Patients With Chronic Heart Failure and Reduced Ejection FractionInsights From the PARADIGM-HF Study (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) Wilson NadruzJr, MD, PhD, Brian L. Claggett, PhD, John J. McMurray, MD, Milton Packer, MD, Michael R. Zile, MD, Jean L. Rouleau, MD, Akshay S. Desai, MD, MPH, Karl Swedberg, MD, Martin Lefkowitz, MD, Victor C. Shi, MD, Margaret F. Prescott, PhD and Scott D. Solomon, MD Wilson NadruzJrWilson NadruzJr From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Brian L. ClaggettBrian L. Claggett From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , John J. McMurrayJohn J. McMurray From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Milton PackerMilton Packer From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Michael R. ZileMichael R. Zile From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Jean L. RouleauJean L. Rouleau From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Akshay S. DesaiAkshay S. Desai From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Karl SwedbergKarl Swedberg From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Martin LefkowitzMartin Lefkowitz From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Victor C. ShiVictor C. Shi From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author , Margaret F. PrescottMargaret F. Prescott From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author and Scott D. SolomonScott D. Solomon From Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (W.N., B.L.C., A.S.D., S.D.S.); Department of Internal Medicine, University of Campinas, Campinas, Brazil (W.N.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.M.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.R.Z.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); and Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.C.S., M.F.P.). Search for more papers by this author Originally published29 Nov 2016https://doi.org/10.1161/CIRCULATIONAHA.116.024976Circulation. 2016;134:1785–1787Circulating levels of natriuretic peptides (NP) are inversely related to body mass index (BMI), and obese patients with heart failure (HF) have lower brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations than nonobese patients.1,2 These observations have raised concerns about the prognostic value of NP in patients with HF with an elevated BMI. Prior observational studies suggested that NP may retain their capacity to predict mortality across all BMI categories in HF with individuals with reduced ejection fraction.3,4 Nevertheless, these studies included a relatively small number of events and did not evaluate additional cardiovascular end points. Because it remains uncertain whether BMI may influence the prognostic utility of NP in patients with HF, we examined the influence of BMI on the predictive value of NT-proBNP and BNP in patients with reduced ejection fraction from the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255).The design and primary results of the PARADIGM-HF trial have been previously described.5 The patients randomized in the trial (n=8399) were required to have a plasma BNP ≥150 pg/mL or an NT-proBNP ≥600 pg/mL or, if they were hospitalized for HF within the previous 12 months, a BNP ≥100 pg/mL or an NT-proBNP ≥400 pg/mL. The present study included patients with available BMI data and who had BNP and NT-proBNP locally measured at the time of screening (n=8217). It considered the primary outcome of the PARADIGM-HF trial, the composite of death from cardiovascular causes or a first hospitalization for HF, as the study outcome. The patients were categorized into 4 groups according to BMI: <25.0 (nonoverweight/obese; n=2536); 25.0 to 29.9 (overweight; n=3116); 30.0 to 34.9 (obese; n=1694); and ≥35.0 kg/m2 (moderately/severely obese; n=871). BNP and NT-proBNP were divided into quartiles within the whole studied population. The trial was approved by the ethics committee at each participating institution, and all the patients provided written informed consent.Multivariable Cox proportional hazards models were used to evaluate the relationship between NP quartiles and primary outcome within each BMI category and to assess the potential interaction between NP quartiles and BMI categories for the studied outcome. The incremental value of NP quartiles when added to clinical covariates for the primary outcome was evaluated with Harrell’s C-statistic considering the whole follow-up period, and continuous net reclassification improvement and integrated diagnostic improvement 2 years after randomization. The covariates included in the analyses were age, sex, and variables that were selected by forward stepwise selection, including all baseline variables reported in the primary manuscript as candidate covariates.5The patients had a mean age of 64±11 years, 78% men, and a mean BMI of 28.0±5.6 kg/m2. NP levels were inversely related to BMI (P for trend <0.001 for NT-proBNP and BNP; Figure). Adjusted Cox-regression analyses showed that over a median of 27 months follow-up, NP levels were predictive of the primary outcome in all BMI categories, but the association was weaker in the highest BMI group (P for interaction=0.030 for NT-proBNP; P=0.058 for BNP). Furthermore, the incremental value of NP levels when added to clinical variables was diminished in the highest BMI quartile, as assessed by Harrell’s C-statistic, net reclassification improvement, and integrated diagnostic improvement (Figure).Download figureDownload PowerPointFigure. Relationship between NT-proBNP and BNP quartiles and the primary outcome evaluated by Cox-regression models and incremental value of natriuretic peptides for the primary outcome according to body mass index categories. During a median follow-up period of 27 [17–35] months, there were 1999 primary outcomes [incidence rate (95% CI) = 11.9 (11.4–12.4) per 100 person-years] in the total sample. Cox-regression analyses were adjusted for the following clinical covariates: age, sex, race, New York Heart Association class, ejection fraction, heart rate, blood pressure, diabetes, estimated glomerular filtration rate, atrial fibrillation, previous heart failure hospitalization and myocardial infarction, diuretics and β-blockers use, and sacubitril/valsartan treatment. NT-proBNP and BNP were divided into quartiles within the whole studied sample. NT-proBNP quartiles: Q1=10–889; Q2=890–1620; Q3=1622–3234; Q4=3236–84 353 pg/mL. BNP quartiles: Q1=1–154; Q2=154–253; Q3=253–470; Q4=471–10 282 pg/mL. BMI indicates body mass index; BNP, Brain Natriuretic Peptide; CI, confidence interval; IDI, integrated diagnostic improvement; Inc. rate, incidence rate reported as 100 person-years; IQR, interquartile range; NRI, net reclassification improvement; and NT-proBNP, N-Terminal Pro-Brain Natriuretic Peptide. *P<0.001. †After adding natriuretic peptide quartiles to clinical covariates.Few studies have addressed the impact of BMI on the prognostic value of NP in patients with an established diagnosis of reduced ejection fraction. Horwich et al3 reported that BNP predicted 1-year death or urgent heart transplantation across all BMI levels in 316 patients. Likewise, Frankenstein et al4 found that NT-proBNP had a similar ability to predict all-cause mortality in all BMI categories in 618 patients, followed for a median period of 37 months. In the present report, we found that higher baseline levels of NP were consistently associated with cardiovascular death or HF hospitalization in all BMI categories, supporting the notion that NP are useful prognostic tools across the BMI spectrum. Nevertheless, in our dataset, which had a much larger sample size with more diverse outcomes than prior reports,3,4 the ability of NT-proBNP and BNP to predict prognosis was attenuated in subjects within the highest BMI category, suggesting diminished prognostic ability of NP among moderately/severely obese patients.Wilson Nadruz Jr, MD, PhDBrian L. Claggett, PhDJohn J. McMurray, MDMilton Packer, MDMichael R. Zile, MDJean L. Rouleau, MDAkshay S. Desai, MD, MPHKarl Swedberg, MDMartin Lefkowitz, MDVictor C. Shi, MDMargaret F. Prescott, PhDScott D. Solomon, MDSources Of FundingThis study was funded by Novartis. Dr Nadruz was supported by the Brazilian National Council for Scientific and Technological Development grant 249481/2013–8.DisclosuresThe PARADIGM-HF trial was funded by Novartis. Dr McMurray received compensation while participating in the PARADIGM-HF study from Novartis. Dr Packer received consulting fees from Novartis. Dr Zile received honoraria from Novartis for participation in the executive committee. Dr Rouleau is a consultant for Novartis. Dr Desai is a consultant for Novartis, St. Jude Medical, Merck, and Relypsa; and has received travel support and grants from Novartis. Dr Swedberg is an advisory board member and has received honoraria from Novartis. Drs Lefkowitz, Shi, and Prescott are employees of Novartis. Dr Solomon is a consultant for and has received grants from Novartis. The other authors report no conflicts of interest.FootnotesCirculation is available at http://circ.ahajournals.org.Correspondence to: Scott D. Solomon, MD, Brigham and Women’s Hospital, Cardiovascular Medicine, Cardiovascular Division, 75 Francis St, Boston, MA 02445. E-mail [email protected]