대한진단검사의학회지 : 제 25 권제 5 호 25 Korean J Lab Med 25; 25: 3-5 임상화학 Access 2 및 AxSYM 에의한 BNP 검사와 Triage BNP 현장검사법과의비교 강소영 서진태 김명희 이우인 이희주 경희대학교의과대학진단검사의학교실 Evaluation of BNP Assays with Access 2 and AxSYM BNP in Comparison with Point-of-Care Triage BNP assay So-Young Kang, M.D., Jin-Tae Suh, M.D., Myung-Hee Kim, M.D., Woo-In Lee, M.D., and Hee-Joo Lee, M.D. Department of Laboratory Medicine, KyungHee University, College of Medicine, Seoul, Korea Background : B-type natriuretic peptide (BNP) is a sensitive and specific marker used widely for the detection of ventricular disorder such as congestive heart failure (CHF). Recently, the manufacturer of Triage BNP assay has developed the liquid type BNP reagent for the usage on the Beckman Coulter Immunoassay Systems such as Access 2. We performed comparison study between Triage BNP assay, Access 2 Triage BNP assay, and AxSYM BNP assay. Methods : The precision study of Access 2 Triage BNP and AxSYM BNP was performed with 5 levels of pooled plasma from 1 to 2, ng/l. The correlation study of Access 2 Triage BNP and AxSYM BNP with Triage BNP assay was done by regression analysis and Bland-Altman analysis with 11 patient samples. The patients were classified and compared using medical decision value of 1 ng/l and final diagnosis. Results : The within-day coefficients of variation (CVs) of Access 2 Triage BNP and AxSYM BNP were less than 1% in all levels of pooled plasma. Both of Access 2 Triage BNP (y=.93x+.17, r=.95) and AxSYM BNP (y=1.9x+7.6, r=.97) showed good correlation with Triage BNP assay. Bland Altman analysis revealed that the difference was increased in proportion to BNP concentration in high concentration. However, the discrepancy of classification of patients was less than 8% when patients were classified with medical decision level of 1 ng/l. In the comparison of BNP levels among different disease groups, CHF group showed significantly higher BNP levels than angina and other disease groups. Conclusions : The Access 2 Triage BNP and AxSYM BNP were showed reliable performance and comparable result with Triage BNP assay. However, the discrepant result found in high concentration should be improved by standardization between different assay methods or instruments. (Korean J Lab Med 25; 25: 3-5) Key Words : B-type natriuretic peptide, Access 2, AxSYM 서 심부전은호흡곤란같은비특이적인증상과이학적소견을보접수 : 24년 12월 22일접수번호 : KJLM1825 수정본접수 : 25년 8월 16일교신저자 : 서진태우 13-72 서울시동대문구회기동 1 경희의료원진단검사의학과전화 : 2-958-8671, Fax: 2-958-869 E-mail: suhjt@hitel.net 론 이므로, 일상적인검사나심전도및방사선검사만으로는정확한진단을내리기에불충분하며 [1], 좌심실부전을찾아내는데표준방법으로알려진심초음파는응급상황에서의사용이제한적이어서심부전의신속하고정확한진단은어려울수밖에없다 [2]. 심부전에대한정확하고신속한진단에이용할표지자로 natriuretic peptide가제시되었고, 그중에서 B-type natriuretic peptide (BNP) 는용적확장과압력과부하에대한반응으로심실의심근세포에서분비되기때문에다른 natriuretic peptide보다심실질환에예 3
Access 2 및 AxSYM 에의한 BNP 검사와 Triage BNP 현장검사법과의비교 31 민하고특이적인표지자로알려졌다. 이후 BNP의농도가뉴욕심장협회의심부전분류및예후와상관관계가있는것이알려지면서울혈성심부전의진단에널리사용되고있다 [2-8]. 현재사용중인 BNP 검사중미국식의약품안전청 (Food and Drug administration, FDA) 공인을받아사용중인검사로현장검사용 Triage BNP assay (Biosite Inc., San Diego, USA) 가시판중이며이는형광면역법을측정원리로하는정량검사법이다. EDTA로항응고처리된혈장이나전혈을이용하여 5-5, ng/l 의측정범위를가지며 15분이내의빠른시간에비교적간단히정량결과를얻을수있다는장점이있으나, 검사과정및보고의전과정이자동화되지않았다는점, 고가의비용및변이계수가 1% 를초과하는재현성등의한계점이있다 [9]. 최근 Triage BNP assay의제조사에서 Access, Access 2, Synchron LXi 725 및 Unicel D I 8 등의 Beckman Coulter Immunoassay System에사용가능한 Triage BNP 액상시약을개발하였기에본원에서사용중인자동화된화학발광면역검사장비인 Access 2 (Beckman Coulter Inc., Fullerton, USA) 에적용시키고자하였다. 또한, 미립자효소면역검사법을이용하는 AxSYM (Abbott Laboratories, Abbott Park, USA) BNP 검사와 Access 2 Triage BNP 검사의정밀도, 최소측정한계및기존장비와의상관성등의수행능력을비교하고, 검사방법에따른 BNP 측정치의차이가환자분류에미치는영향을살펴보고자하였다. 장비로각제조사의지시대로 BNP를측정하였다. 이로부터얻은결과를이용하여검사방법간상관성을보기위해 MedCalc version 7.5 (MedCalc software, Mariakerke, Belgium) 를이용하여회귀검정과 Bland-Altman 분석을시행하였다 [1]. 또한이들측정값들에대해임상적 cut-off치인 1 ng/l을기준으로적용하여환자들을분류할경우세가지검사방법간분류상의불일치를조사하였다. 3. 통계 11명의환자들중 1명의병록조사가가능하였으며이를바탕으로환자들의진단에따라울혈성심부전군, 급성심근경색군, 협심증군, 부정맥군및기타질환군의 5군으로분류하여서로다른질환군간에 BNP 농도가의미있는차이를보이는지검사방법별로살펴보았다. 통계처리는 SPSS version 11. (SPSS Inc., Chicago, USA) 을이용하여 ANOVA 및다중비교 (Tukey s honestly significant difference test) 를시행하였고, 아울러심부전진단의정확성을비교하기위해 receiver operating characteristics (ROC) curve 분석을시행하였다. 결과 대상및방법 1. 검사일내정밀도 1. 검사일내정밀도 Access 2로 Triage BNP 시약 (Biosite Inc.) 을사용하는방법 ( 이하 Access 2 Triage BNP) 과 AxSYM 장비로 AxSYM BNP 시약 (Abbott Laboratories) 을사용하는방법 ( 이하 AxSYM BNP) 에대해약식으로각각검사일내정밀도검사를시행하였다. 저농도에서고농도까지 (1-2, ng/l) 다양한농도로준비된 5단계의모음혈장 (pooled plasma, Pool No. 1-5) 을이용하여각농도별로 1회씩측정한후 3분이상의간격을두고다시각농도별로 1회씩반복검사를시행하여얻은결과로평균, 표준편차및변이계수를구하는방법으로검사일내정밀도를평가하였다. 2. Triage BNP assay와의비교 BNP 검사가의뢰된 11명의환자들의 EDTA 혈장검체로기존의 BNP 검사법인 Triage BNP assay로제조사의지시대로검사를시행하여얻은값을기준결과치로사용하였다. 시험관내소실을최소화하기위해검체채취후 4시간이내에혈장을분리하여 -2 에냉동보관된검체를해동시켜화학발광면역검사법을이용한 Access 2와미립자효소면역검사법을이용한 AxSYM 농도별로시행한 BNP의검사일내정밀도평가에서 Access 2 Triage BNP 및 AxSYM BNP의변이계수는저농도에서고농도에걸친모든농도에서 1% 미만으로나타났다 (Table 1). 2. 기존검사방법과의비교 검사방법간상관성을보기위해 Access 2 Triage BNP 측정값과 AxSYM BNP 측정값들을기존의 BNP 검사법인 Triage Table 1. Within-day precision of BNP assays at various levels Pool No.* Access 2 Triage BNP SD CV (%) AxSYM BNP SD CV (%) 1 17.2.96 5.6 NT NT NT 2 86.5 2.1 2.3 NT NT NT 3 178.5 4.27 2.4 NT NT NT 4 412.6 7.77 1.9 445.9 21.37 4.8 5 2142.4 21.35 1. 1337.2 68.72 5.1 *The different pooled plasma were used in Access 2 Triage BNP and AxSYM BNP. Abbreviations: BNP, B-type natriuretic peptide; SD, standard deviation; CV, coefficient of variation; NT, not tested.
32 강소영 서진태 김명희외 2 인 5, 4, Access 2 BNP 4, 3, 2, 1, N=17 y=.93x+.17 r=.95 AxSYM BNP 3, 2, 1, N=82 y=1.9x+7.58 r=.97 1, 2, 3, 4, Triage BNP A 1, 2, 3, 4, Triage BNP B 15 1 +1.96 SD 1 +1.96 SD 5 65.1 Triage-Access 2 5-5 -1 74.7-3.8-1.96 SD -82.2 Triage-AxSYM -5-1 -15-23.3 +1.96 SD -111.8-15 -2-2 1 2 3 4 5 6 BNP C -25 1 2 3 4 5 6 BNP D Fig. 1. Method comparison analysis. (A, B), Regression analysis. The solid line indicates the regression line, and the dashed line indicates the line of unity. (A) Triage BNP assay vs Access 2 Triage BNP; (B) Triage BNP assay vs AxSYM BNP. (C, D), Bland-Altman analysis. The solid line indicates the mean difference between methods, and the dashed lines indicate 95% confidence intervals for the differences. (C) Triage BNP assay vs Access 2 Triage BNP; (D) Triage BNP assay vs AxSYM BNP. Table 2. Agreement of classification among three BNP assays according to plasma BNP concentration BNP Triage BNP Access 2 Triage BNP <1 1 AxSYM BNP <1 1 <1 44 44 39 5 1 34 1 33 1 33 Discrepant rate 1/78 (1.3%) 6/78 (7.7%) Kappa inter-rate.97.85 agreement (95% CI.92-1.3) (95% CI.73-.96) BNP assay와비교한결과는 Fig. 1과같다. Triage BNP assay (x) 와 Access 2 Triage BNP (y) 에대한회귀분석결과기울기.93±.3, y절편.17±19.96, S y x (standard deviation of residuals) 186.43 (r=.95) 이었으며, Triage BNP assay (x) 와 Ax- SYM BNP (y) 에대한회귀분석결과기울기 1.9±.3, y절편 7.58±22.77, S y x 181.17 (r=.97) 로나타났다. Bland-Altman 그래프에서 Triage BNP assay 결과와 Access 2 Triage BNP 및 AxSYM BNP 결과와의차이값의평균이각각 17.1 ng/l (95% CI, 388.6~-354.3), -37.2 ng/l (95% CI, 334.6~-48.9) 로나타났으며, Triage BNP assay 농도가증가할수록비례적으로 Access 2 Triage BNP 및 AxSYM BNP와의차이가음의방향으로커지는양상을보였다 (Fig. 1C, D). 11명의환자중세가지검사방법이모두적용됐던환자는 78 명이었고이들의 BNP 검사결과를이용하여울혈성심부전선별을위한임상적 cut-off인 1 ng/l을기준으로환자들을분류했을때검사방법간의분류불일치는 Table 2와같다. Triage BNP assay와 Access 2 Triage BNP 간에는 78명중 1명 (1.3%) 으로 kappa inter-rate agreement 값이.97이었고, Triage BNP assay와 AxSYM BNP 간에는 78명중 6명 (7.7%) 의분류상불일치를보였고 kappa값은.85였다. Triage BNP assay에서 1 ng/l 미만이었으나 Access 2 Triage BNP나 AxSYM BNP에서
Access 2 및 AxSYM 에의한 BNP 검사와 Triage BNP 현장검사법과의비교 33 Table 3. BNP and standard deviation of three different BNP assay methods according to disease group CHF AMI Angina Arrhythmia Other dis. P* N 16 11 33 7 33 Sex (M:F) 4:12 9:2 16:17 5:2 15:18 Age (mean±sd) 67.6 (±1.7) 65.2 (±6.7) 65.3 (±8.1) 65.3 (±13.9) 53.7 (±2.) Triage BNP assay 525.9 (±782.4) 56.7 (±68.) 92.5 (±113.5) 11.4 (±57.6) 136.2 (±43.5).5 Access 2 Triage BNP 578.5 (±126.2) 246.7 (±31.4) 88.1 (±97.2) 125.9 (±65.3) 124.9 (±377.7).18 AxSYM BNP 634.7 (±931.4) 59. (±564.6) 118.8 (±141.9) 177. (±23.) 221. (±663.9).98 *Tested by ANOVA, By multiple comparison with Tukey s honestly significant difference test, there were significant differences between CHF group and other disease group (Triage BNP assay, P=.46 and Access 2 Triage BNP, P=.2) and between CHF group and angina group (Triage BNP assay, P=.2 and Access 2 Triage BNP, P=.1). Abbreviations: CHF, congestive heart failure; AMI, acute myocardial infarction. Sensitivity 1 8 6 4 2 1-Specificity AUC 95% CI Access2.83.72-.91 AxSYM.85.74-.92 Triage.82.71-.91 2 4 6 8 1 이를보였으나, AxSYM BNP에서는질환군간 BNP 농도는의미있는차이를보이지않았다 (P=.98) (Table 3). 또한 Triage BNP assay와 Access 2 Triage BNP로검사한경우울혈성심부전군은협심증군과기타질환군간에의미있는 BNP 농도차이를보였고, 급성심근경색군이나부정맥군과는의미있는차이를보이지않았다. 한편 AxSYM BNP의경우질환군들간에통계적으로의미있는차이를보이지않았다. 울혈성심부전진단에대한 Triage BNP assay, Access 2 Triage BNP 및 AxSYM BNP의 ROC curve 분석에서 area under the curve (AUC) 는각각.82,.83 및.85로나타났다. 또한 Triage BNP assay와 Access 2 Triage BNP, Triage BNP assay와 AxSYM BNP, Access 2 Triage BNP와 AxSYM BNP 간의 ROC curve 비교에서 P값이각각.81,.43,.65로의미있는차이를보이지않고비슷한수행능력을나타냈다 (Fig. 2). Fig. 2. Receiver operating characteristics (ROC) curve analysis for Triage BNP assay (Triage), Access 2 Triage BNP (Access2), and AxSYM BNP (AxSYM) in differentiating congestive heart failure (CHF) from non-chf disease. Abbreviations: AUC, area under the curve; CI, confidence interval. 1 ng/l 이상으로측정된경우가각각 예및 5예였고, Triage BNP assay에서 1 ng/l 이상이었으나 Access 2 Triage BNP 나 AxSYM BNP에서 1 ng/l 미만으로측정된경우가각각 1예씩나타났다. 3. 질환군간 BNP 농도비교 병록조사가가능했던 1명의환자들의진단은울혈성심부전군 16명, 급성심근경색군 11명, 협심증군 33명, 빈맥등의부정맥군 7명및기타질환군 33명의분포를보였으며기타질환군에는심장초음파검사상심기능이정상인고혈압환자 11명, 간질경련환자 3명, 종양 3명, 결핵 2명, 갑상선항진증 2명, 급성신부전 1명, 염증성장질환 1명, 임상적및검사실소견상이상이없었던환자 1명이었다. Triage BNP assay와 Access 2 Triage BNP는서로다른질환군간에 P값이각각.5 및.18로통계적으로의미있는차 고찰 BNP는심근세포에서생산, 분비되는 32개의아미노산단백으로이루어진신경호르몬으로서 134개의아미노산단백인 preprob- NP가 18개의아미노산단백인 probnp를거쳐 1-76 아미노산의 NH2 terminal-probnp (NT-proBNP, probnp) 와생물학적활성형태인 77-18 아미노산의 COOH terminal-probnp (CTproBNP, BNP) 로분열되어심근세포로부터 probnp와 BNP가혈류로동량분비되나 probnp에비해 BNP의반감기가짧기때문에혈중농도의차이를보인다 [9, 11, 12]. BNP는심부전, 신부전및간경화증등으로인한용적과부하로인해심실벽의팽창자극을받을경우생산및분비가항진되므로다른 natriuretic peptide보다특이적으로심실질환을반영하며, 분비된 BNP는교감신경계및여러호르몬계와의상호작용을통한나트륨배뇨및이뇨항진, 혈관확장효과를통해혈압을낮추는역할을하게된다 [11-14]. 혈장 BNP 측정의임상적효용은울혈성심부전의진단과평가에이용되며또한급성관상동맥질환환자의위험도평가및호흡곤란을보이는환자의감별진단에이용될수있다 [11, 12]. BNP 농도는다양한생리적요소들에의해영향을받으며, 그중
34 강소영 서진태 김명희외 2 인 에서도연령과성별이결정적차이를초래한다. 즉, 심부전유무에상관없이연령이증가할수록또한여성일수록 BNP 농도가증가하기때문에연령이나성별에맞는참고범위를설정해야하는데 Triage BNP assay나 AxSYM BNP를사용하는대부분의검사실에서는임상적결정치인 1 ng/l을 cut-off로사용하고있다 [15, 16]. 기존의 Triage BNP assay는 5-5, ng/l의측정범위를가지며 29.1 및 1128 ng/l 농도에서변이계수가각각 1.4% 와 15.8% 이며 [17], AxSYM BNP의경우측정범위가 -4, ng/l이고다양한농도에서 1% 이하의변이계수를보인다 [18]. 본연구에서는 Access 2 Triage BNP와 AxSYM BNP의일내정밀도평가결과에서두방법모두변이계수가 1% 이내로나타나현장검사인 Triage BNP assay 검사가갖는재현성부족이라는단점을극복할수있는방법으로평가되었다. 또한 Triage BNP assay 측정값을기준결과치로간주한검사방법간비교에서 Access 2 Triage BNP와 AxSYM BNP 모두상관계수가.95 이상으로나타났고 1에근접한기울기를갖는회귀방정식을보이는등검사간상관성이우수하게평가되었다. 그러나검사방법결과간의차이를보는 Bland-Altman 분석에서 Triage BNP assay 농도가증가할수록 Access 2 Triage BNP 및 AxSYM BNP 농도가더높게측정되었는데, Access 2 Triage BNP의경우 2-3 ng/ L, AxSYM BNP의경우 1 ng/l 이상에서검사방법결과간차이가비례적으로증가하는경향을나타냈다. Access 2 Triage BNP는 Triage BNP assay 제조사인 Biosite사에서 Triage BNP assay 검사에사용중인동일항체를사용하여제조한 BNP 액상시약을사용하며, AxSYM BNP는 Triage BNP assay 결과에맞도록할당치를맞춘참고물질로조정된 calibrators를사용한다 [18]. 따라서이세가지방법은서로일치된결과를보여야하나, 본연구에서처럼고농도로올라갈수록검사결과의차이가증가하는등의불일치현상이나타나는데이는사용된 calibrator 및항체의반응성의차이 [19] 와검사방법의차이에서비롯되므로, 다양한검사방법간의일치를위한표준화작업이앞으로더이루어져야할것으로생각된다. 본연구에서 Triage BNP assay와 Access 2 Triage BNP의경우울혈성심부전군은협심증군과기타질환군간에의미있는 BNP 농도차이를보였으나급성심근경색군이나부정맥군과는유의한차이를보이지않았다. 특히급성심근경색후 24시간동안 BNP 농도가급속히증가했다가안정화되며, 경색후 1일에서 4 일사이의 BNP 농도는예후와상관성이있어 BNP 농도는급성심혈관질환환자의위험도평가에이용될수있다 [2]. 이는기존의보고에서처럼 BNP 단독으로는울혈성심부전진단을할수없으며, 본연구에서처럼비슷한 BNP 증가를보였던급성심근경색등다른질환을배제하기위해여러임상적정보및검사소견들과함께해석해야함을시사한다. 한편 AxSYM BNP의경우질환군들간에 BNP 농도는통계적으로의미있는차이를보이지않았으나울혈성심부전의진단적정확성을보기위한 ROC 분석상으로는 Triage BNP assay나 Access 2 Triage BNP와유의한차이가없었다. Triage BNP assay 결과와비교했을때, 고농도로갈수록 Access 2 Triage BNP 및 AxSYM BNP의불일치가증가하고, BNP 1 ng/l을 cut-off로환자를분류했을때 Triage BNP assay와의분류일치율이 AxSYM BNP보다 Access 2 Triage BNP에서더높았으나, 두방법모두기존의 Triage BNP assay 와우수한일치도를보이면서보다우수한정밀도를보이며, ROC 곡선분석상울혈성심부전을진단하는데있어비슷한수행성적을보인다는점과아울러현재로서는본연구에서시행한세가지검사법중어느방법이가장참값에가까운측정치를제공하는지알수없다는점을고려했을때각검사실에서는각자의필요와조건에맞는방법을선택하는것이바람직할것으로생각된다. 요약배경 : 울혈성심부전의진단에널리이용되는 B-type natriuretic peptide (BNP) 는심실질환에예민하고특이적인표지자이다. 최근현재사용중인현장검사용 Triage BNP assay 제조사에서 Access 2 등의 Beckman Coulter 면역분석장비에서사용가능한 Triage BNP 액상시약이개발되어이의수행성적을평가하기위해 Triage BNP assay와자동화면역검사장비인 Access 2와 AxSYM과비교하였다. 방법 : Access 2 Triage BNP와 AxSYM BNP 측정의정밀도와 Triage BNP assay와의상관성을분석하였다. 정밀도는 1-2, ng/l사이의 5단계의모음혈장을이용하였고, 상관성평가를위해 11 개의검체를사용하여 Triage BNP assay 결과와 Access 2 Triage BNP 및 AxSYM BNP 결과를비교하여회귀분석과 Bland-Altman 분석을시행하였다. 임상적결정치인 1 ng/l을기준으로환자들을분류하여검사방법간불일치정도를살펴보았고, 또한질환별로도분류하여 BNP 농도의차이를비교하였다. 결과 : 농도별로시행한 BNP의검사일내정밀도평가에서 Access 2 Triage BNP 및 AxSYM BNP의변이계수는모든농도에서 1% 미만이었고, Triage BNP assay와의상관성검사에서 Access 2 Triage BNP는 y=.93x+.17 (r=.95), AxSYM BNP는 y=1.9x+7.6 (r=.97) 으로우수한상관성을보였다. Bland-Altman 분석상고농도로갈수록두방법모두 Triage BNP assay와의불일치가심화되어이보다높게측정되는경향을보였으나 1 ng/l을결정치값으로분류할경우 Access 2 Triage BNP는 1.3%, AxSYM BNP는 7.7% 의분류불일치를나타냈다. Triage BNP assay와 Access 2 Triage BNP의경우울혈성심부전군은협심증군과기타질환군간에의미있는 BNP 농도차이를보였으나급성심근경색군이나부정맥군과는차이를보이지않았다. 결론 : Access 2 Triage BNP나 AxSYM BNP는정밀도및
Access 2 및 AxSYM 에의한 BNP 검사와 Triage BNP 현장검사법과의비교 35 기존의 Triage BNP assay와의상관성이나울혈성심부전의진단수행능력에있어서우수한것으로평가되었다. 그러나검사방법및검사장비의차이에따라나타나는고농도에서의불일치증가현상은표준화과정으로개선되어야할것으로생각되었다. 참고문헌 1. Maisel A. B-type natriuretic peptide measurements in diagnosing congestive heart failure in the dyspneic emergency department patient. Rev Cardiovasc Med 22; 3 (Suppl 4): S1-7. 2. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 22; 347: 161-7. 3. Maeda K, Tsutamoto T, Wada A, Hisanaga T, Kinoshita M. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. Am Heart J 1998; 135: 825-32. 4. Clerico A, Iervasi G, Del Chicca MG, Emdin M, Maffei S, Nannipieri M, et al. Circulating levels of cardiac natriuretic peptides (ANP and BNP) measured by highly sensitive and specific immunoradiometric assays in normal subjects and in patients with different degrees of heart failure. J Endocrinol Invest 1998; 21: 17-9. 5. Krishnaswamy P, Lubien E, Clopton P, Koon J, Kazanegra R, Wanner E, et al. Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction. Am J Med 21; 111: 274-9. 6. Cheng V, Kazanagra R, Garcia A, Lenert L, Krishnaswamy P, Gardetto N, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 21; 37: 386-91. 7. Maisel AS, Koon J, Krishnaswamy P, Kazenegra R, Clopton P, Gardetto N, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. Am Heart J 21; 141: 367-74. 8. Harrison A, Morrison LK, Krishnaswamy P, Kazanegra R, Clopton P, Dao Q, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med 22; 39: 131-8. 9. Azzazy HM and Christenson RH. B-type natriuretic peptide: physiologic role and assay characteristics. Heart Fail Rev 23; 8: 315-2. 1. Bland JM and Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 37-1. 11. Clerico A and Emdin M. Diagnostic accuracy and prognostic relevance of the measurement of cardiac natriuretic peptides: a review. Clin Chem 24; 5: 33-5. 12. Prontera C, Emdin M, Zucchelli GC, Ripoli A, Passino C, Clerico A. Analytical performance and diagnostic accuracy of a fully-automated electrochemiluminescent assay for the N-terminal fragment of the pro-peptide of brain natriuretic peptide in patients with cardiomyopathy: comparison with immunoradiometric assay methods for brain natriuretic peptide and atrial natriuretic peptide. Clin Chem Lab Med 24; 42: 37-44. 13. Maisel AS. The diagnosis of acute congestive heart failure: role of BNP measurements. Heart Fail Rev 23; 8: 327-34. 14. Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997; 96: 59-16. 15. Wieczorek SJ, Wu AH, Christenson R, Krishnaswamy P, Gottlieb S, Rosano T, et al. A rapid B-type natriuretic peptide assay accurately diagnoses left ventricular dysfunction and heart failure: a multicenter evaluation. Am Heart J 22; 144: 834-9. 16. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 22; 4: 976-82. 17. Kazanegra R, Cheng V, Garcia A, Krishnaswamy P, Gardetto N, Clopton P, et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail 21; 7: 21-9. 18. Mueller T, Gegenhuber A, Poelz W, Haltmayer M. Preliminary evaluation of the AxSYM B-type natriuretic peptide (BNP) assay and comparison with the ADVIA Centaur BNP assay. Clin Chem 24; 5: 114-6. 19. Apple FS, Panteghini M, Ravkilde J, Mair J, Wu AH, Tate J, et al. Quality specifications for B-type natriuretic peptide assays. Clin Chem 25; 51: 486-93. 2. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, et al. The prognostic value of B-type natriuretic pepyer M. Preliminary evaluation of the AxSYM B-type natriuretic peptide (BNP) assay and comparison with the ADVIA Centaur BNP assay. Clin Chem 24;5:114-6.tide in patients with acute coronary syndromes. N Engl J Med 21; 345: 114-21.