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B-type natriuretic peptides in chronic obstructive pulmonary disease: a systematic review Hawkins, Nathaniel M; Khosla, Amit; Virani, Sean A; McMurray, John J V; FitzGerald, J M Jan 10, 2017

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RESEARCH ARTICLE Open AccessB-type natriuretic peptides in chronicobstructive pulmonary disease:a systematic reviewNathaniel M. Hawkins1* , Amit Khosla1, Sean A. Virani1, John J. V. McMurray2 and J Mark FitzGerald3AbstractBackground: Patients with chronic obstructive pulmonary disease (COPD) have increased cardiovascular risk.Natriuretic peptides (NP) in other populations are useful in identifying cardiovascular disease, stratifying risk,and guiding therapy.Methods: We performed a systematic literature review to examine NP in COPD, utilising Medline, EMBASE, andthe Cochrane Library.Results: Fifty one studies were identified. NP levels were lower in stable compared to exacerbation of COPD, andsignificantly increased with concomitant left ventricular systolic dysfunction or cor pulmonale. Elevation occurredin 16 to 60% of exacerbations and persisted in approximately one half of patients at discharge. Cardiovascularcomorbidities were associated with increased levels. Levels consistently correlated with pulmonary artery pressure andleft ventricular ejection fraction, but not pulmonary function or oxygen saturation. NP demonstrated high negativepredictive values (0.80 to 0.98) to exclude left ventricular dysfunction in both stable and exacerbation of COPD, butrelatively low positive predictive values. NP elevation predicted early adverse outcomes, but the association with longterm mortality was inconsistent.Conclusion: NP reflect diverse aspects of the cardiopulmonary continuum which limits utility when applied inisolation. Strategies integrating NP with additional variables, biomarkers and imaging require further investigation.Keywords: Natriuretic peptides, Chronic obstructive pulmonary disease, Heart failure, BiomarkersBackgroundCOPD is the only major cause of mortality for whichdeath rates continue to rise. There remains a lack ofobjective measures to risk-stratify patients, standardizedmanagement of comorbidities, and therapies thatprolong life. One third of deaths in COPD relate tocardiovascular disease, equaling or exceeding pulmonary-related mortality [1–3]. Cardiovascular therapies areproven to reduce morbidity and mortality, yet areunderutilized because disease is unrecognized [4]. Simple,generalizable and cost-effective strategies are thereforeneeded to identify cardiovascular disease (and particularlyheart failure) to improve outcomes in COPD.The U.S. Food and Drug Administration and inter-national guidelines have highlighted the need for bio-marker development in COPD [5]. However, developmentis challenging and translation into clinical practice hasbeen largely unsuccessful [6, 7]. Given the recognized car-diovascular phenotypes within COPD, [8] the use of estab-lished cardiovascular biomarkers merits exploration. Thenatriuretic peptides (NP) B-type natriuretic peptide (BNP)and N-terminal fragment (NT-proBNP) are powerfulindependent predictors of death and adverse events in HF,a broad range of cardiovascular conditions, and even inasymptomatic individuals in the community [9]. In pri-mary care patients at high cardiovascular risk, intensivemanagement of those with a raised BNP detected on sys-tematic screening reduced the incidence of heart failureand left ventricular dysfunction [10]. NP may therefore* Correspondence: nat.hawkins@ubc.ca1Division of Cardiology, University of British Columbia, BC Centre forImproved Cardiovascular Health, St. Paul’s Hospital, 1081 Burrard Street,Vancouver V6Z 1Y6, BC, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Hawkins et al. BMC Pulmonary Medicine  (2017) 17:11 DOI 10.1186/s12890-016-0345-7prove useful in identifying cardiovascular disease, stratify-ing risk, and guiding therapy in COPD.However, pulmonary disease itself, pulmonary hyper-tension, and right ventricular strain are also associatedwith NP elevation. This may undermine the utility of NPin COPD across the spectrum of potential applications:reduced diagnostic accuracy for HF; impaired risk strati-fication due to transient changes or weak associationwith predictors of prognosis; and by correlation with fac-tors unresponsive to treatment. We therefore undertooka systematic review to direct future research and providehealthcare providers with a concise, critical, unbiasedsynthesis of the expanding body of literature. The studyaims were to define the prevalence, distribution, associa-tions, prognostic implications, and diagnostic accuracyof peptide elevation in COPD.MethodsParticipants, outcomes and study designsPreferred Reporting Items for Systematic reviews andMeta-Analyses (PRISMA) guidelines were followed. Thepopulation of interest was patients with COPD receivingnatriuretic peptide testing. The outcome of interest wasNP, including: levels and proportion elevated in differentCOPD populations, stratified by COPD severity (stabledisease, acute exacerbation (AECOPD), associated corpulmonale); thresholds used to define abnormal; cor-relations between NP and measures of ventricular andpulmonary function; risk associated with NP; andaccuracy of NP in diagnosing HF. All study designsincluding cohort, case-control and cross-sectionalwere accepted.Search strategy and data collectionMEDLINE (from 1990), EMBASE (from 1990), and theCochrane Library were searched to June 2015, limited toadult humans, without date or language restriction. Searchterms were selected by consensus and iterative databasequeries. Medical Subject Headings (MeSH) and Emtreeterms were identified from keyword mapping and pub-lished literature. COPD was identified using MeSH(pulmonary disease, chronic obstructive; bronchitis,chronic), Emtree (chronic obstructive lung disease; chronicbronchitis), and keywords. NP were identified using MeSH(natriuretic peptides), Emtree (brain natriuretic peptide),and keywords. Terms and keywords were combined ac-cording to the requirements of the database. The searchstrategy is outlined in Appendix 1. No review protocol wasregistered or published. The search identified 440 articlesin Medline and EMBASE, totalling 276 records after dupli-cate removal (Fig. 1). Case reports, reviews and conferenceabstracts were excluded. Two reviewers (NH and AK)screened titles and abstracts (binary yes/no) with reconcili-ation through discussion. Studies fulfilling the participant,outcomes and study design criteria were included.Studies involving patients with different pulmonarydiseases (as opposed to COPD) or only HF were ex-cluded (Fig. 1). Variables of interest were decided apriori and expanded iteratively after pilot. Excelspreadsheets were employed as data extraction formsand populated directly by both reviewers (NH andAK). The following information was extracted: biblio-graphic details, sample size and number of centers,population, baseline characteristics and comorbidities,pulmonary function, NP outcomes.Study qualityIn accordance with the Cochrane Collaboration andInstitute of Medicine guidance, risk of bias in observa-tional studies was assessed in selected components withempirical evidence and strong clinical or theoreticalgrounds. A quality scale was not utilized as many havelimited development methodology, validation, arbitraryweightings and inconsistent relationships with effect sizes.7 bias domains were selected (selection, misclassification,performance, detection, reporting, information and con-founding), based on the Cochrane Collaboration Risk ofBias Tool and Handbook and Agency for HealthcareResearch and Quality RTI Item Banks,[11–13] Judgementof low, high or unclear risk of bias was assigned for eachdomain (Appendices 2, 3 and 4).Synthesis and analysisThe evidence is presented as a narrative synthesis giventhe heterogeneous populations, diverse objectives andoutcomes examined, varying assays and thresholds, andpoorly defined confounding factors. Most importantly,Fig. 1 Flow diagram of study selectionHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 2 of 17the summary measures presented in many studies(median and ranges) require transformation for meta-analysis. We explored multiple transformation methods,[14–16] all of which declined in accuracy with increasingskew and underestimated the variance by up to half. Weidentified 4 main groups (stable COPD/BNP, stableCOPD/NT-proBNP, exacerbation COPD/BNP, exacerba-tion COPD/NT-proBNP). Median/IQR was more oftenreported in the exacerbation and NT-proBNP studiesdue to skewed distributions (Table 1). Thus transformationfor meta-analysis would introduce major error into alreadylarge variances in a systematic manner.ResultsFifty one studies were identified, of which 31 were pub-lished within the preceding 5 years and 46 within thelast decade.Study qualityRisk of bias in many domains was low with respect tomeasurement of NP. Studies were typically small, pro-spective, without interventions or exposures, cohort orcross-sectional in design, and measured NP in all patientsusing commercial validated assays. However, approxi-mately 50% of studies exhibited selection bias, 20% lackedobjective definition of COPD, and 40% failed to report suf-ficient information to facilitate interpretation of NP levels(e.g. presence of HF) (Appendices 3 and 4).Natriuretic peptides levels in patients with COPDStable COPDBNP and NT-proBNP levels were normal or only mildlyelevated in stable ambulatory patients in whom HF wasexcluded or infrequent (Table 1). In the seven studieswith controls, NP levels were mildly elevated (albeit sig-nificantly) in two studies and similar to controls in theremainder [17–23]. The three largest prospective cohortstudies in stable COPD included a higher proportion ofpatients with left ventricular systolic dysfunction (LVSD)(prevalence 11 to 15%) [24–26]. In these patients, NPwere elevated approximately 5 fold compared to thosewithout LVSD. Natriuretic peptides were also signifi-cantly elevated in patients with cor pulmonale accordingto various definitions [27–29].Eight studies examined NP in stable patients stratifiedby severity of COPD according to the Global Initiative forChronic Obstructive Lung Disease (GOLD) (Appendix 5).The 5 largest studies observed no significant differ-ence in median or mean levels with severity, whilethe 3 smallest studies reported significantly higherNP levels in patients with more severe COPD. Asingle study in 170 patients reported the proportionof patients with elevated BNP stratified by COPDseverity [30]. NT-proBNP was elevated in GOLDstages I to IV in 21, 21, 23 and 28% of patients, re-spectively (p = 0.87).Acute exacerbation COPDAverage natriuretic peptide levels were modestly higherduring exacerbations than in stable patients in three typesof comparison (Table 1): relative to reported valuesfrom other studies in stable COPD, compared tostable controls recruited in the same study, [31, 32]and compared to repeated estimates in the same pa-tient outside of an exacerbation episode [33–39]. Thetime course of biomarker release relative to exacerba-tion was rarely investigated. In 127 consecutive hospi-talizations, NT-proBNP was elevated in 60% ofpatients at admission and persisted in 28% at dis-charge [34]. The largest study with multiple timepoints found no significant decline in average NT-proBNP sampled on days 3, 7, 14 and 35 after the oc-currence of exacerbation [38]. Of interest, significantelevation in NT-proBNP in that study were limited topatients with a history of ischaemic heart disease.Subgroups with comorbiditiesIn subgroups of patients with comorbidities associatedwith NP release, levels were significantly increased com-pared to those without comorbidities. These includedischaemic heart disease, [38, 40] pulmonary emboli, [41]arrhythmia, [32] aortic stenosis, [25] pulmonary hyper-tension, [42] renal impairment [32, 43]. However, thesecomorbidities were rarely reported or searched for sys-tematically. For example, atrial fibrillation was onlyreported in 7 studies.Correlates and predictors of elevated natriuretic peptidesin COPDThe most consistent association was between NP andpulmonary artery pressure, with correlation coefficientsranging from 0.28 to 0.68, typically being around 0.5(Table 2). In most studies with echocardiography,NP elevation was associated with left ventricularejection fraction (LVEF) among patients with stableand exacerbation of COPD, [25, 26, 32, 35, 37, 39]even in the absence of raised pulmonary artery pres-sures. Right ventricular function was rarely charac-terized, and then using a variety of measuresincluding ejection fraction,[19] tricuspid annularplane systolic excursion (TAPSE), [37] right ventricu-lar diameter and hypokinesia [29, 31]. Heterogeneityand small sample sizes limits interpretation.The relationship between NP and FEV1 or PaO2 wasinconsistent. Similar to the evidence stratifying byCOPD severity, the smaller studies observed significantcorrelations between NP and both FEV1 or PaO2. How-ever, correlation coefficients in the two largest studies ofHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 3 of 17Table1NatriureticpeptideslevelsinpatientswithCOPDStablediseasenAgeMean±SDFEV 1FEV 1%PredSmokingcurrent/past/neverExacer-bationdefinition%LVSDorHF(EF)RenalfunctionAF%NP(pg/ml)NPlevelsmean±SD/SE*ormedian(IQR)Controlsmean±SDormedian(IQR)PvaluevsCOPDNPlevelssubgroupsmean±SDormedian(IQR)Fujii[71]2168±50.9445nr-exnormalnrBNP8±2*--Cabanes[72]1765±61.3nrnr-exnrexcBNP14±12--Hemlin[73]2566±10.83428/72/0-exnormalexcBNP21±5*--Papaioannou[74]4966±9nr4249/nr/nr-exnrexcBNP31(15–70)--Kim[75]2273±6nr46nr-nrnrnrBNP41±60--Anderson[17]9368±2nr7034/66/0-1(<40%)nrnrBNP29±6*26(20–32)p=0.46-Gemici[18]1753±11nr55nr-exnormalnrBNP21±1613±11p>0.05-Rutten[24]20073±5nr84nr-15(≤45%)nr9BNP39(17–79)-LVSD135(41–317),p<0.001Rutten[24]20073±5nr84nr-15(≤45%)nr9NT–BNP117(72–210)-LVSD560(169–1572),p<0.001Watz[30]17064±7nr5642/nr/nr-3(≤50%)nrnrNT–BNP67(40–117)--Murphy[76]2566±90.954088/12/0-12(<55%)excrenalfailurenrNT–BNP113(147)-LVSD296,p=0.01Gale[25]14067±131.2nr82/11/6-11(<45%)Crmean92μmol/l9NT–BNP44±132-LVSD537(119–2243),p=0.03Macchia[26]21870±701.253924/72/4-14(≤40%)5%renalfailurenrNT–BNP103(49–273)-LVD677(384–1682),p<0.0001Patel[40]11868±91.224936/nr/nr-nrnrnrNT–BNP12(6–21)-Boschetto[21]2369±4nr78nr-exeGFRmean66nrNT–BNP121(59–227)50(43–51)p=ns-Wang[22]8070±6nrnrnr-exeGFRmean73nrNT–BNP245(196–336)101(56–150)-Rubinsztajn[77]8165±7nr52nr-nrnrnrNT–BNP190±234--Sanchez[78]7165±7nr3910/90/0-exnrexcNT–BNP79±70--Beghe[23]7069±8nr60nr-exnrnrNT–BNP115(50–364)50(43–51)p<0.05-Ozdemirel[19]3161±81.605739/55/6-exexcrenalfailureexcNT–BNP100±8248(35)p=0.003Bando[27]1475±11.0957nr-nrexcrenalfailurenrBNP13±3*7±1CP81±13,p<0.001Hawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 4 of 17Table1NatriureticpeptideslevelsinpatientswithCOPD(Continued)Bozkanat[28]3859±7nr40nr-exnrnrBNP21±109±3CP74±36,p<0.001Anar[29]80nrnr32nr-nrexcrenalfailurenrNT–BNP58±64-CP869±1135,p<0.001Coldea[79]7259±71.8nr69/nr/nr-exeGFRmedian57nrNT–BNP204(69–311)-CP1323(234–2567),p<0.001ExacerbationXie[80]17472±6nr47nrHospitalnrnrnrBNP254(100–521)7(5–10)-Escande[81]2966±10nr3727/nr/nrHospitalexeGFRmedian92excBNP37(21–78)--Gariani[47]5776±8nrnrnrHospital23(<50%)nr28BNP420±426--Abroug[46]14868[15]nrnrnrICU18(<50%)Crmed93μmol/lnrNT–BNP398(673)-HF5374(8243),p<0.0001Martins[82]14977±11nrnrnrHospital51HF17%renalfailure37NT–BNP268(482)--Marteles[83]9974±8nrnrnrHospitalexexcrenalfailurenrNT–BNP1289±1875--Chang[44]24472±110.813533/63/3Hospitalex9%renalfailurenrNT–BNP243±498--Hoiseth[45]9972±90.9133nrHospital14HFCrmed65μmol/l10NT–BNP423(264–909)HF1554,p=0.102Ouanes[43]12067[15]nrnrnrICU17LVSD58%renalfailurenrNT–BNP3796±5448LVD3313(4603),p<0.001Akpinar[41]17271±101.5056nrHospitalnrexcrenalfailurenrNT–BNP1188±3233ExacerbationvsStableControlKanat[31]3065±7nr67nrHospitalexexcrenalfailurenrBNP405(184–2108)101(63–342)p=0.0001RVD1460(857–3018),p=0.01Wang[32]31175nrnrnrED16(<45%)eGFRmedian739NT–BNP840(248–3334)208(187–318)HF4828(2044–9204),p<0.001ExacerbationvsStablePhaseStolz[33]20870±100.934145/47/8ED108%renalfailurenrBNP65(34–189)45(25–85)p<0.001CM144(58–269),p<0.001Inoue[35]60nrnrnrnrMixed6(<50%)nrnrBNP80±16*41±9p=0.004Nishimura[36]6175±8nr81nrHospital6(<50%)nrnrBNP55(27–129)18(10–45)p<0.0001Hawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 5 of 17Table1NatriureticpeptideslevelsinpatientswithCOPD(Continued)Lee[37]18710.836nrHospital28LVSDexcrenalfailurenrNT–BNP630(220–2500)147(7–980)p=0.04Patel[38]9872±81.145220/nr/nrAntibiotics±steroidsnrnrnrNT–BNP36±5723±39p<0.001ElMallawany[39]2058±9nrnrnr/nr/25ICU20LVSDnrnrNT–BNP1298±849539±485p=0.03HF:6777±1434AFatrialfibrillation;BNPbrainnatriureticpeptide;CMcardiomyopathy;Crcreatinine;eGFRestimatedglomerularfiltrationrate(mL/min/1.73m2);excexcluded;ICUintensivecareunit;IHD,ischaemicheartdisease;LVDleftventriculardysfunction;LVSDleftventricularsystolicdysfunction;nrnotreported;NT-proBNPN-terminalproBNP;RVDrightventriculardysfunctionHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 6 of 17Table2CorrelatesofnatriureticpeptideinpatientswithCOPDStudynNatriureticpeptideFEV 1PaO2TroponinCRPLVEFPAPRVdysfunctionEchoAnar[29]80stableNT–BNPr=−0.06p=0.73r=−0.14p=0.40––r=−0.22p=0.40r=0.39p=0.01RVDr=0.36p=0.02Bozkanat[28]38stableBNPr=−0.65p<0.001r=−0.70p<0.001–––r=0.68p<0.001–Chi[84]61stableNT–BNPr=−0.56p<0.001r=−0.35p=0.03–––r=0.44p=0.001–Hemlin[73]25stableBNP–––––r=0.54p=0.02–Hwang[85]31stableNT–BNPr=−0.26p=ns––––r=0.59p=0.002–Inoue[35]60stableBNPp=nsp=ns––r=−0.41p=0.02r=0.5p=0.004–Kim[75]22stableNT–BNPp=ns––––r=0.51p=0.02–Mansour[86]57stableBNPr=−0.49p<0.01r=−0.44p<0.05–––r=0.49p<0.01–Ozdemirel[19]31StableBNPr=−0.44p=0.001––––r=0.65p=0.02RVEFr=0.09p=0.51Kanat[31]37AECOPDBNP–p=ns––––r=0.474p=0.008Lee[37]18AECOPDNT-BNP––––r s=−0.76p<0.001p=nsTAPSEr s=0.51p=0.04ElMallawany[39]20AECOPDNT–BNP–r=0.19p=0.41–r=0.09p=0.71r=−0.58p=0.007––Nishimura[36]54AECOPDBNP––––r s=−0.22p=0.108––Ouanes[43]120AECOPDNT–BNP––––r=−0.296p=0.008––Wang[32]311AECOPDNT–BNP––––r=−0.35p<0.001r=0.283p<0.001–NoEchoChang[44]244AECOPDNT-BNP–p=nsr s=0.46p<0.001r s=0.16p=0.01–––Fujii[71]21StableBNPr=−0.30p=nsr=−0.39p=ns–––r=0.28p=ns–Hoiseth[45]99AECOPDNT-BNP––r=0.34p=0.0006––––Martins[82]173AECOPDBNP––r=0.06p=0.4––––Patel[38]98AECOPDNT–BNP––r=0.50p<0.001r=0.46p<0.001–––Stolz[33]208AECOPDBNPr=0.104p=0.222r=0.115p=0.191–r=0.246p=0.001–––BNPbrainnatriureticpeptide;FEV 1forcedexpiratoryvolumeinonesecond;FVCforcedvitalcapacity;GFRglomerularfiltrationrate;IL–8interleukin8;LVEFleftventricularejectionfraction;NT-proBNPN-terminalproBNP;PaO2arterialpartialpressureofoxygen;PAPpulmonaryarterypressure;PVRpulmonaryvascularresistance;rsSpearman’srankcorrelationcoefficient;RVrightventricle;RVDrightventriculardiameter;RVEFrightventricularejectionfraction;TAPSEtricuspidannularplanesystolicexcursionHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 7 of 17208 and 80 patients were not significant (respectivelyFEV1 r = 0.104 and PaO2 0.115; FEV1 r = 0.06 and PaO20.14). A modest significant association was observed be-tween NP and troponin in three studies (r = 0.34 to 0.50)[38, 44, 45].Prevalence of natriuretic peptide elevation and thresholdsemployed to define abnormalDifferent strategies have been employed to define ‘abnormal’(Table 3): ROC curve analysis to balance accuracy in pre-dicting specific outcomes; measuring central tendency anddispersion of normal controls (e.g. mean ± 2 SD); manufac-turer recommendation; existing publications or investiga-tor selection. The proportion of patients with elevated NPaccording to these heterogeneous thresholds ranged from15 to 71% in stable patients, and 16% to 60% during ex-acerbation. Five studies employed receiver operating curveanalysis to determine optimal thresholds for detecting leftventricular dysfunction [24, 32, 39, 43, 46]. However, onlyone of these studies actually reported the prevalence of anelevated level according to these thresholds (approximately50% in stable patients) [24]. Moreover, identical thresholdsin different studies yielded very different frequencies ofelevation. NT-proBNP >125 pg/ml occurred in 23% and51% of stable patients in two studies [24, 30]. Likewise,NT-proBNP >125 pg/ml occurred in 16%, 27% and 44% ofAECOPD in three studies [37, 38, 44].Accuracy of natriuretic peptides in detecting heart failurein patients with COPDNatriuretic peptides were always significantly elevated inpatients with COPD and concurrent HF or LVSD com-pared to those without (Table 1). However, very few studiesexamined predictive accuracy to identify HF or LVSD, withjust a single study in patients with stable COPD (Table 4)[24]. Four natriuretic peptide assays produced compar-able results in 200 stable elderly patients with a clinicaldiagnosis of COPD. Each test excluded HF with reason-able accuracy (all negative predictive values above 0.85,with positive predictive values approximately 0.4). InTable 3 Thresholds used to define abnormal in patients with COPDNatriuretic peptide Threshold (pg/ml) Method of selecting threshold Proportion elevated (%)StableInoue [35] BNP 34 2 SD from mean of normal control 37Bozkanat [28] BNP 36 investigator selection nrRutten [24] BNP NT–BNP 35 125 ROC curve 49 51Watz [30] NT–BNP 125 manufacturer reference range 23van Gestel [49] NT–BNP 500 cited review article (Jelic 2006) [87] 17Macchia [26] NT–BNP 160 median nrAndersen [42] NT–BNP 95 ROC for echo pulmonary hypertension 71Anar [29] NT–BNP 125/450 (age specific) manufacturer reference range 15Rubinsztajn [77] NT–BNP 125 manufacturer reference range 44Ozdemirel [19] NT–BNP 84/155 (gender specific) nr nrExacerbationLee [51] BNP 88 ROC for survival 39Gariani [47] BNP 500 guidelines 30Abroug [46] NT–BNP 1000 and 2500 ROC rule out and in LV dysfunction nrSanchez-Marteles [88] NT–BNP 500 ROC for survival 53Chang [44] NT–BNP 220 pmol/l local laboratory (also Lee 13) [37] 27Hoiseth [45] NT–BNP 2500 based on Abroug [46] 18Marcun [34] NT–BNP – age/sex adjusted 95 percentile 60Ouanes [43] NT–BNP 1000/2000 (renal specific) ROC for LV dysfunction nrLee [37] NT–BNP 220 pmol/l local laboratory (also Chang 11) [44] 44Wang [32] NT–BNP 935 ROC for LV dysfunction nrPatel [38] NT–BNP 220 pmol/l based on Chang [44] 16El Mallawany [39] NT–BNP 900 ROC for LV dysfunction nrBNP B-type natriuretic peptide; COPD chronic obstructive pulmonary disease; LV left ventricular; NT-proBNP N-terminal proBNP; ROC receiver operator characteristic;SD standard deviationHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 8 of 17three studies of patients with AECOPD, NP demon-strated high negative predictive values (0.80 to 0.98) toexclude left ventricular dysfunction applying thresholds ex-ceeding the manufacturers’ guidance (Table 4) [32, 46, 47].However, as in the stable population the positive pre-dictive values were relatively low. Two studies alsoassessed ability to detect systolic and diastolic dys-function separately [24, 47]. The receiver operatingcharacteristic areas and overall accuracy in the latterwere lower though remained acceptable.Prognostic significance of natriuretic peptides in COPDWe identified 12 studies (6 stable and 6 exacerbation ofCOPD) reporting the association between NP and prog-nosis, in which the prognostic significance of elevationwas inconsistent (Table 5). Among stable patients, theassociation between NP and survival over 1 to 4 yearsfailed to remain significant after multivariable adjust-ment in 3 studies [25, 35, 48]. However, NT-proBNP>500 pg/ml predicted one year mortality in 144 patientswith predominantly mild to moderate COPD andTable 5 Prognostic significance of natriuretic peptides in COPDn Follow up Echo(%)Heart failuredetailsNatriuretic peptidethresholdEndpoints Unadjusted risk Adjusted riskStableInoue [35] 60 3 years 53 6% <50% BNP > 34.2 deathexacerbationnot significant increased not significant HR 3.8(1.2–12.7) p = 0.02Gale [25] 140 1 year 100 11% EF < 45% highest vs lowestquartiledeathhospitalizationRR 3.0 (p = 0.001) not significant notsignificantWaschki[48]170 48 months 100 – – death HR 1.47 (1.05–2.06) 1.16 (0.97–1.39)Andersen[42]117 2.8 years 100 – NT-proBNP <95 ng/L death HR 0.29 (0.09–0.97) p = 0.04 –van Gestel[49]144 1 year 100 ex EF≤ 40% NT-proBNP>500 pg/mldeath HR 4.5 (1.5–13.5) HR 7.7 (1.6–37.4)Zeng [50] 220 22 months – 26% HF – death – 1.61 (1.27–2.06)ExacerbationStolz [33] 208 2 year 75 10% LVSD per 100 pg/ml death ICUadmissionnot significant 1.12 (1.03–1.22)not significant1.13 (1.0–1.24)Lee [51] 67 inpatient – – BNP >88 pg/ml death – OR 21.2 (2.5–180.4)Chang[44]244 1 year 0 acute cardiacdisease exNT-proBNP >220pmol/Ldeath 30 daydeath 1 yearOR 9.0 (3.1 – 26.2) p < 0.0011 year not significantOR 7.5 (1.9–28.9) p = 0.0041 year not significantMarcun[34]127 6 month 100 13% EF < 55%42% DDage/genderadjusteddeathhospitalizationHR 5.49 (1.25-24.00)HR 1.34 (0.84-2.63)HR 4.20 (1.07-14.01)HR 1.48 (0.60-3.69)Medina[52]192 1 year 0 exclude prior NT-proBNP>588 pg/mldeath OR 3.90 (1.46-10.47)p = 0.006OR 3.30 (1.11–9.85)p = 0.034Hoiseth[45]99 median1.9 years0 21% vs 9%tertile 3 vs 1tertile 3 vs 1 death HR 6.9 (3.0 – 16.0)p < 0.0001HR 3.2 (1.3–8.1) p = 0.012BNP B-type natriuretic peptide; COPD chronic obstructive pulmonary disease; DD diastolic dysfunction; EF left ventricular ejection fraction; HF heart failure;HR hazard ratio; LVSD left ventricular systolic dysfunction; NT-proBNP N-terminal pro BNP; OR odds ratio; RR relative riskTable 4 Accuracy of natriuretic peptides in predicting left ventricular systolic dysfunctionn Population %LVSD (LVEF) Threshold Left ventricular dysfunction NPV PPVRutten [24] 200 primary care elderly 15 (≤45%) BNP 35 pg/ml NT-BNP125 pg/mlpanel adjudicated systolicdysfunction~0.95 ~0.4Abroug [46] 148 intensive care unit 18 (<50%) NT-BNP 1000 pg/ml panel adjudicated systolic ordiastolic dysfunction0.94 0.78Gariani [47] 57 hospitalization retrospective 23 (<50%) BNP 500 pg/ml systolic dysfunction diastolicdysfunction0.88 0.80 0.47 0.41Wang [32] 311 hospitalization 16 (<45%) NT–BNP 935 pg/ml panel adjudicated systolic ordiastolic dysfunction0.98 0.47BNP B-type natriuretic peptide; LVEF left ventricular ejection fraction; LVSD left ventricular systolic dysfunction; NPV negative predictive value; NT-proBNP N-terminalproBNP; PPV positive predictive valueHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 9 of 17preserved LVEF (>40%) undergoing major vascular sur-gery (adjusted HR 7.7 [95% 1.6–37.4]) [49]. NT-proBNPwas also associated with all-cause mortality in a largercohort of 220 elderly men with COPD (adjusted HR1.61 [1.27–2.06]), although 26% of that cohort haddocumented HF [50].In patients with AECOPD, NP independently pre-dicted short term outcomes including intensive care unitadmission, [33] inpatient and 30 day mortality [44, 51].Median BNP was also significantly higher in failed (in-patient death or early re-hospitalisation) compared tosuccessful discharges following AECOPD hospitalization(median (IQR) 261 (59–555) vs 49 (24–104) pg/ml) [36].The relationship with longer term survival was lesscertain. Natriuretic peptides failed to predict mortalityat 1 and 2 years in 244 and 208 consecutive patientshospitalized or presenting to the emergency depart-ment with exacerbation [33, 44]. However, elevatedNP were independently associated with increased mortal-ity at 6 months, 1 year and nearly 2 years in three subse-quent studies (respectively HR 4.2, OR 3.3 and HR 3.2)[34, 45, 52].DiscussionCauses of natriuretic peptide elevation in patients withand without COPDMyocardial stretch in either ventricle consequent tovolume or pressure overload increases NP levels [53].Causes include heart failure with reduced and pre-served ejection, [54, 55] right ventricular failure, [56]pulmonary emboli, [41, 57] acute coronary syndromes,[58, 59] valvular heart disease, [60] and arrhythmias[61]. Advancing age and renal dysfunction are also as-sociated with elevated NT-proBNP concentrations [62].Many of these factors are present in stable COPD andcommon non-infective precipitants of exacerbation[32, 41, 63]. The presence and extent of each factorvaries significantly from patient to patient, and is largelyindependent of COPD severity or acute right ventriculardysfunction. Thus NP levels are higher during acuteexacerbation or chronic decompensation (cor pulmo-nale) than stable disease, and exhibit significant variabilitywith skewed distributions.By systematically searching and aggregating individualstudies, our review highlights several new and consistentobservations which suggest NP release is multifactorialwith limited direct relationship to COPD. First, NPlevels are increased even in some patients with mildCOPD without arterial hypoxaemia, severe pulmonaryhypertension or right ventricular dysfunction. Second,levels are stable or exhibit only a minor gradient withincreasing COPD severity. Third, the magnitude ofthe correlation coefficients (r) suggests only approxi-mately 25% to 50% of the variance (r2) in NP isattributable to any single variable. Moreover, correl-ation between left and right ventricular function islikewise modest (LVEF and TAPSE r = 0.46 in onestudy), [37] indicating only around 20% of the vari-ance in function of either ventricle is explained bythe function of the other.Prognostic significance of natriuretic peptidesIndividual studies have concluded that NP may beuseful in risk stratifying patients with COPD [34, 44, 49].However, the overall literature has not previously beensummarized. The association with longer term outcomeswas inconsistent in both stable and exacerbation popu-lations. Our findings highlight many of the challengesin developing biomarker strategies: relatively smallsample sizes; variable performance in heterogeneouspopulations; and failure to replicate findings from der-ivation to validation cohorts [7]. At present there isinsufficient evidence to recommend routine risk strati-fication using NP.The more consistent prediction of early outcomes fol-lowing exacerbations suggests that NP are more stronglyassociated with acute pathologies rather than COPD it-self [33, 44, 51]. The precise causes remains unclear, asrisk associated with many acute events improves withtime e.g. HF, PE. Nevertheless, unrecognised LVSD un-doubtedly underpins many adverse outcomes. While NPlevels were typically modest, [44] up to one fifth of pa-tients with AECOPD had marked elevation indicative ofprobable left heart failure (although acute right ventricu-lar strain remains possible) [45]. Moreover, the signifi-cant unadjusted association between NT-proBNP andmortality in one study was nulled after adjustment forLVEF and valvular disease [25]. This hypothesis is fur-ther supported by the high prevalence of unrecognisedheart failure in imaging and autopsy studies, [64] andthe improved outcomes associated with angiotensin con-verting enzyme inhibitors and beta-blockers in observa-tional COPD studies [65, 66].Clinical application of natriuretic peptides in COPDNatriuretic peptides exhibit lower diagnostic accuracyfor HF in COPD than in populations with acute dys-pnoea, [67, 68] due to greater overlap of NP distribu-tions in the respective states to be distinguished: levelsare elevated in stable and exacerbation of COPD, andlower in stable compared to acute HF. The thresholdproviding adequate sensitivity and negative predictivevalue must generate sufficiently few false positives tointegrate into systems of care, be cost-effective, and im-prove outcomes. However, the positive predictive valuesin the 3 stable or exacerbation populations we identifiedranged from 0.4 to 0.47. This compares unfavourablywith a recent meta-analysis of NP in the acute careHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 10 of 17setting, which reported positive predictive values rangingfrom 0.67 and 0.64 for BNP and NT-proBNP respect-ively at the guideline recommended lower thresholds,rising to 0.85 and 0.80 respectively for mid-range values[69]. The resulting increase in false positive results willincrease demand on imaging services to confirm orrefute the diagnosis.Directions for future researchTo improve generalizability and interpretation, futurestudies should use validated assays in consecutivepatients, and standardized definitions for COPD, HF andcomorbidities. Detailed cardiovascular profiles andimaging are needed to systematically define pathologiescontributing to NP elevation. Levels should be reportedusing guideline and manufacturer recommendedthresholds, for both the overall population and stratifiedaccording to presence or absence of predictors of NPelevation, particularly left ventricular dysfunction. Largerstudies examining cause-specific outcomes are needed.Integrating NP with clinical variables and simpleinvestigations such as electrocardiograms should beevaluated to reduce false positive results and developcost-effective screening strategies. The goal of improv-ing outcomes is particularly challenged by the incon-sistent prognostic implications of NP in COPD instudies to date. The greatest incremental prognosticand therapeutic value is likely in populations withunrecognized heart failure and cardiovascular diseaseamenable to treatment [34, 45, 70].LimitationsMost of the identified studies were single centre withlimited numbers of patients and endpoints. The patientpopulations, assays and cutoffs for NP, and definitions ofLVSD and HF were heterogeneous. No study systematic-ally defined causes of NP elevation, and the proportionamenable to therapy e.g. arrhythmia, ischaemia, LVSD,pulmonary emboli. These comorbidities will stronglyinfluence every outcome examined, from symptoms toprognosis. The causes of death in relation to NP eleva-tion also require clarification.ConclusionsNatriuretic peptides are often increased in patients withCOPD, reflecting three complex interwoven aspects ofthe cardiopulmonary continuum: left heart systolic anddiastolic dysfunction; pulmonary vascular and right heartremodelling; and global cardiovascular risk and comor-bidities. The additional peptide elevation during exacer-bations is likely a marker of both acute strain andvarying degrees of underlying cardiopulmonary dis-ease: in some patients effectively a stress test and har-binger of future adverse events. The balance of thesepathophysiologic abnormalities within populations isunclear. The goal is to untangle this heterogeneity, toidentify individuals at greatest risk and facilitate tar-geted interventions. Strategies integrating NP withadditional variables, biomarkers and imaging requirefurther investigation.Appendix 1Search strategy.Combined Medline and Embase search strategy.Medline and Embase1) (exp pulmonary disease, chronic obstructive/or expbronchitis, chronic/) USE mesd2) (exp *chronic obstructive lung disease/or *expchronic bronchitis) USE emezd3) ((obstruct*) adj2 (pulmonary or lung* or airway* orairflow* or bronch* or respiratory*)).ti,ab.4) (COPD or COAD or COBD).mp.5) or/1–46) (exp natriuretic peptides) USE mesd7) (exp brain natriuretic peptide) USE emezd8) (natriuretic adj2 peptide$ or BNP or proBNP).mp.9) or/6–810) 5 and 911) limit 10 to humans12) limit 11 to yr = ‘1990-Current’13) 12 not exp newborn/not exp infant/not exp child/not exp adolescent/14) 13 not (case report* or review* or comment* oreditorial* or note* or conference abstract*).pt15)..dedup 14Appendix 2Description of 7 risk of bias domains assessed.Table 6 Risk of bias domains assessedSelection Is there consecutive or random participantsampling?Misclassification Are key inclusion/exclusion criteria clearly statedand defined by valid and reliable measures?Performance Did the study vary from the protocol proposed bythe investigators, and was there appropriate ethicalapproval?Detection Is the study design prospective, retrospective, ormixed?Reporting Are important primary outcomes missing from theresults?Information Were valid and reliable measures used consistentlyacross all study participants to assess outcomes,exposures or interventions?ConfoundingInterpretationWere important confounding and effect modifyingvariables accounted for in the design and/oranalysis?Hawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 11 of 17Appendix 3Risk of bias summary.Chart demonstrating overall proportion of studies clas-sified as low, unclear or high risk of bias within the 7domains.Fig. 2 Risk of bias summaryHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 12 of 17Appendix 4Table reporting risk of bias within the 7 domains foreach study.Table 7 Risk of bias in individual studiesSelection Misclassify Performance Detection Reporting Information ConfoundingAbroug 06 [46] Low High Low Low Low Low LowAgoston-Coldea 14 [79] High Low Low Low Low Low LowAkpinar 14 [41] Low Low Low Low Low Low HighAnar 12 [29] High Low High Low Low Low HighAndersen 12 [42] High Low Low Low High Low HighAnderson 13 [17] Low Low Low Low Low Low LowBando 99 [27] High High Low Low Low Low HighBeghe 13 [23] High Low Low Low Low Unclear HighBoschetto 13 [21] Low Low Low Low Low Unclear LowBozkanat 05 [28] High High Low Low Low Low LowCabanes 01 [72] Low Low Low Low Low Low LowChang 11 [44] Low Low Low Low Low Low LowChi 12 [84] High Low Low Low Low Low LowEl Mallawany 14 [39] High High Low Low Low Low HighEscande 14 [81] High Low Low Low Low Unclear LowFujii 99 [71] High Low Low Low Low Low LowGale 11 [25] Low Low Low Low Low Low LowGariani 11 [47] High High Low High High Low HighGemici 08 [18] High Low Low Low Low Low LowHemlin 07 [73] High Low Low Low Low Unclear LowHoiseth 12 [45] Low Low Low Low Low Low LowHwang 07 [85] High Unclear Unclear High Unclear Unclear UnclearInoue 09 [35] High Low Low Low Low Low HighKanat 07 [31] Low Low Low Low Low Low LowKim 10 [75] High Low Low Low Low Low HighLee 04 [51] High Low Unclear High High Unclear HighLee 13 [37] High Low Low Low Low Low LowLopez-Sanchez 13 [78] Low Low Low Low Low Unclear HighMacchia 12 [26] Low Low Low Low Low Low LowMarcun 12 [34] Low Low Low Low Low Low HighMartins 09 [82] High High Low High High Unclear HighMurphy 09 [76] Low Low Low Low Low Low LowNishimura 14 [36] Low Low Low Low Low Unclear HighOuanes 12 [43] Low Low Low Low Low Low LowOzdemirel 14 [19] Low Low Low Low Low Low LowPapaioannou 10 [74] Low Low Low Low Low Low LowPatel 12 [40] High Low Low Low High Low HighPatel 13 [38] High Low Low Low Low Low HighRubinsztajn 13 [77] Low Low High High Low Low HighRutten 07 [24] Low High Low Low Low Low LowSanchez-Marteles 09 [83] Low Low Low Low Low Low LowHawkins et al. BMC Pulmonary Medicine  (2017) 17:11 Page 13 of 17Appendix 5Table reporting natriuretic peptide levels in 8 studiesstratified by COPD severity according to GOLDclassification.AbbreviationsAECOPD: Acute exacerbation of chronic obstructive pulmonary disease;BNP: B-type natriuretic peptide; COPD: Chronic obstructive pulmonarydisease; FEV1: Forced expiratory volume in 1 s; GOLD: Global Initiative forChronic Obstructive Lung Disease; HF: Heart failure; LVEF: Left ventricularejection fraction (LVEF); LVSD: Left ventricular systolic dysfunction;MeSH: Medical Subject Headings; NP: Natriuretic peptides; NT-proBNP:N-terminal pro B-type natriuretic peptide; TAPSE: Tricuspid annular planesystolic excursionAcknowledgementsOur thanks to Mohsen Sadatsafavi for providing additional comments on themanuscript.FundingThe authors received no financial support in preparation of the manuscript.Authors’ contributionsNMH designed the review, collected data, and drafted the manuscript; AKcollected data and helped draft the manuscript; SV participated in studydesign, interpreted results, and critically revised the manuscript; JJVMinterpreted results and revised critically for intellectual content; JMFconceived the review and revised critically for intellectual content. Allauthors read and approved the final manuscript and take responsibility for allaspects of the work.Availability of data and materialThe datasets during and/or analysed during the current study available fromthe corresponding author on reasonable request.Competing interestsDrs Hawkins, Khosla, Virani, McMurray and FitzGerald have no competinginterests to declare.Consent for publicationNot applicable.Ethics approval and consent to participateNot applicable.Author details1Division of Cardiology, University of British Columbia, BC Centre forImproved Cardiovascular Health, St. Paul’s Hospital, 1081 Burrard Street,Vancouver V6Z 1Y6, BC, Canada. 2Glasgow Cardiovascular Research Centre,University of Glasgow, Glasgow, UK. 3Division of Respiratory Medicine,University of British Columbia and Institute for Heart and Lung Health,Vancouver, Canada.Table 7 Risk of bias in individual studies (Continued)Sanchez-Marteles 10 [88] Low Low Low Low Unclear Low HighStolz 08 [33] Low Low Low Low Low Low Highvan Gestel 10 [49] High Low Low Low Low Low LowWang 11 [20] High Low Low Low Low Low LowWang 13 [22] High High Low Low Low Unclear LowWang 13 [32] Low High Low Low Low Low LowWaschki 11 [48] Low Low Low Low Low Low LowWatz 08 [30] High Low Low Low Low Unclear LowXie 13 [80] Unclear High High Low Low Low HighZeng 13 [50] High Low Low High Low Unclear HighTable 8 Natriuretic peptide levels in patients with COPD stratified by severityn Population Natriureticpeptide(pg/ml)Median or mean peptide level according to GOLD I/II/III/IVSignificant difference across GOLDgroupsRutten [24] 118 stable NT-proBNP ~127/119/136/169 p = NSWatz [30] 170 stable NT-proBNP 69/62/67/73 p = 0.78Inoue [35] 60 stable BNP ~30/30/50/65 p < 0.01van Gestel[49]144 stable NT-proBNP 212/170/352/–Mansour [86] 57 stable BNP excluded/38/60/78 p < 0.05Chi [84] 61 stable NT-proBNP excluded/112/151/250 p = 0.02Nishimura [36] 190 stable BNP 18/26/22/17 p = 0.53Rubinsztajn[77]81 stable NT-proBNP 114/232/155/231 p = NSBNP brain natriuretic peptide; GOLD, Global Initiative for Chronic Obstructive Lung Disease; NT-proBNP N-terminal proBNPHawkins et al. 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