Journal of Laboratory Medicine and Quality Assurance

응급실 내원 환자에서 심장표지자 현장검사 동시 시행의 유용성

Misuk Ji, Hee-Won Moon, Seungman Park, Mina Hur, and Yeo-Min Yun

Additional article information

Abstract

Background:

B-type natriuretic peptide (BNP) levels are elevated in various conditions unrelated to heart failure, such as acute coronary syndrome, and cardiac troponin (cTn) levels may also be elevated in several non-ischemic conditions. This study aimed to evaluate the clinical usefulness of combined cardiac marker testing (BNP and cTnI) with point-of-care devices in patients who presented to the emergency department (ED).

Methods:

Two thousand six hundred and seventy-four consecutive patients who visited the ED from March to August 2013 were included in this study. Cardiac marker testing was performed using the Triage Cardio3 panel (Alere, USA). Electronic medical records were collected on August 2014.

Results:

We found that 22.2% patients had elevated BNP and/or cTnI (12.8% with only elevated BNP, 4.4% with only elevated cTnI, and 5.0% with both elevations). Patients with elevations in both marker levels showed significantly higher admission rate (78.5% vs. 62.7%, P=0.006) and longer length of hospital stay (11 vs. 6 days, P=0.001) than those with only elevated cTnI. Patients with elevations in both marker levels also showed higher admission rate (78.5% vs. 67.3%, P=0.016) and higher BNP levels (430 vs. 194 pg/mL, P<0.001) than those with only elevated BNP.

Conclusions:

Concurrent elevation of BNP and cTnI may be associated with inferior clinical outcome and combined testing of cTnI and BNP levels with high sensitivity would provide important information for assisting management decisions at the ED.

Keywords: Troponin I, B-type natriuretic peptide, Emergency department

INTRODUCTION

B-type natriuretic peptide (BNP) is synthesized in the ventricular myocardium and released into circulation in response to ventricular dilatation and pressure overload [1]. In addition to its roles in the diagnosis, exclusion, and risk stratification of congestive heart failure, BNP can also provide prognostic information in patients with acute coronary syndrome (ACS) [1-3]. Higher BNP levels predict higher risk for death due to post-myocardial infarction and heart failure independent of the status of troponin [1]. Cardiac troponins (cTn) are both sensitive and specific markers of cardiac myonecrosis, and higher levels predict worse outcomes [4-6]. cTn is also elevated in many non-ischemic conditions, including acute and chronic heart failure, myocarditis, critical illness, and sepsis [7]. Elevated cTn levels correlate with adverse prognosis in patients without ACS. cTn values above the 99th percentile of the upper reference limit are suggested as prognostic markers in patients with acute decompensated heart failure [8] or other heart failure [6].

Accordingly, the implementation of multiple biomarker approach, including both cTn and BNP, might be considered in patients with possible ACS at the emergency department (ED). Several point-of-care (POC) devices for cardiac marker testing are currently in use at various sites, including the ED, due to rapid turnaround time and users’ convenience [9,10]. This study aimed to evaluate the clinical usefulness of combined cardiac marker testing with a POC device in unselected patients who present to the ED.

MATERIALS AND METHODS

1. Study Population

From March to August 2013, adult patients (over 18 years-old) who visited the ED of the Konkuk University Medical Center and received simultaneous BNP and cTnI testing with a POC device were included in this study. A total of 2,674 patients were enrolled, and they had symptoms or signs of possible ACS or risk factors. The mean age of all patients was 58.9 years. The institution is a tertiary care community hospital located in Seoul with approximately 50,000 annual ED visits. This study was approved by the institutional review board of the Konkuk University Medical Center (approval no. KUH1200035).

1) Cardiac marker testing

BNP and cTnI were measured by the Triage Cardio3 panel (Alere, San Diego, CA, USA) with a Triage meter device. Cutoff value of BNP was 100 pg/mL [11,12]. For cTnI, the 99th percentile value was 0.02 ng/mL and the cutoff for determination of clinical sensitivity was 0.4 ng/mL according to the manufacturer’s guidelines [11,12]. cTnI values ≥0.03 ng/mL were considered as elevated cTnI, whereas those between 0.03 and 0.4 ng/mL were interpreted as low-level positive, which is indicative of marginally increased cTnI levels [13]. cTnI values above 0.4 ng/mL were interpreted as overtly positive. The cTnI results were divided into 3 groups (negative, low-level positive, and overtly positive). Creatine kinase-myocardial band results were not included in this study. For cTnI, total coefficient of variation at the 99th percentile was 17.0%, and hence, this assay was clinically usable according to the Apple scorecard [14,15].

2) Data collection

Patients’ electronic medical records including diagnosis at the time of admission, admission rate, length of stay, rate of readmission within 3 months, and mortality rates were retrospectively collected on August 2014. Patients showing any positivity for cTnI or BNP were reviewed.

3) Statistical analysis

The IBM SPSS Software ver. 19.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The independent t-test or the Mann-Whitney U-test was used to compare continuous variables, and the chi-square test was used to compare categorical variables. P-values less than 0.05 were considered statistically significant.

RESULTS

1. Distribution of the Emergency Department Patients

The study participants were divided into 4 categories according to the results of cardiac marker testing: BNP elevation only (343, 12.8%), cTnI elevation only (118, 4.4%), both elevations (135, 5.0%), and both negative (2,078, 77.7%) (Fig. 1). In total, 22.3% patients had elevated BNP and/or cTnI. The mean age of these patients was significantly higher than those of subjects who tested negative for both markers (70.7±14.2 versus 54.9±18.4 years, P<0.001).

Figure F1
1)Comparison of double marker elevation with single marker elevationDistribution of patients based on the positivity for two cardiac markers. Five hundred and ninety-six patients (22.3%) had elevated BNP and/or cTnI ...

Distribution of patients based on the positivity for two cardiac markers. Five hundred and ninety-six patients (22.3%) had elevated BNP and/or cTnI concentrations. The 99th percentile of cardiac troponin I is 0.02 ng/mL, and hence, values ≥0.03 ng/mL were considered to be positive. The cutoff for BNP is 100 pg/mL. Abbreviations: BNP, B-type natriuretic peptide; cTnI, cardiac troponin I.

1)Comparison of double marker elevation with single marker elevation

Patients with elevations in both marker levels revealed higher admission rate after the ED visit (78.5% versus 62.7%, P=0.006) and longer length of hospital stay after admission (median [interquartile range], 11 [5-19] versus 6 [3-13] days; P=0.001) than those with only cTnI elevation. The length of hospital stay was further calculated after excluding patients with cerebral infarction, cerebral hemorrhage, gastrointestinal bleeding, or major fractures. The median length of hospital stay was 11 (5-16) and 5.5 (4-11.8) days for patients with elevations in both markers and only cTnI elevation, respectively. The number of excluded patients was 13 for the BNP only elevation group, 12 for the cTnI only elevation group, and 11 for the double elevation group. In addition, patients with elevations in both markers showed higher admission rate after the ED visit (78.5% versus 67.3%, P=0.016), higher BNP levels (430 [228-727] versus 194 [140-322] pg/mL, P<0.001), and shorter length of ED stay (228 [151-345] versus 263 [185-345] minutes, P=0.026) than those with only BNP elevation. Other variables were insignificant (Table 1 and Fig. 2).

Table 1

Clinical and laboratory characteristics in patients with cardiac troponin I and/or B-type natriuretic peptide elevation

Variable Patients with double elevations (N=135) Patients with only cTnI elevation (N=118) Patients with only BNP elevation (N=343)



cTnI (+)/BNP (+) * cTnI (+)/BNP (-) * P-value cTnI (-)/BNP (+) * P-value
Age (yr) 74.2±11.2 61.9±16.8 <0.001 72.4±13.1 0.145
Length of ED stay (min) 228 (151–345) 200 (103-326) 0.112 263 (185–345) 0.026
Admission rate after ED visit (%) 78.5 (106/135) 62.7 (74/118) 0.006 67.3 (231/343) 0.016
Length of hospital stay after admission (day) 11 (5–19) 6 (3–13) 0.001 10 (5–20) 0.761
Readmission rate within 3 months of discharge (%) 17.9 (19/106) 10.8 (8/74) 0.188 16.5 (38/231) 0.737
Mortality rate within 1 year (%) 17.0 (19/112) 17.9 (14/78) 0.860 12.7 (31/245) 0.276
cTnI (ng/mL, half-life about 2 hr) 0.07 (0.04–0.18) 0.05 (0.03–0.19) 0.429 0.01 (0.01–0.01) -
BNP (pg/mL, half-life 20 min) 430 (228–727) 23 (9–46) - 194 (140–322) <0.001

Values are presented as mean±SD, median (interquartile range), or percentage (number of patients/total patients included in the analysis).

Abbreviations: cTnI, cardiac troponin I; BNP, B-type natriuretic peptide; ED, emergency department.

The 99th percentile of cardiac troponin I is 0.02 ng/mL. Thus, values ≥0.03 ng/mL were considered positive. The cutoff for BNP is 100 pg/mL.

P-values were calculated in comparison with the patients with both cardiac marker elevations.

Mortality rate was calculated after excluding the patients with follow-up loss.

Admission rate and length of hospital stay after admission of each group based on the combinatin of cTnI and BNP levels. Length of hospital stay presented as median value and interquartile ranges are as follows: 5–19, 3–13, and 5–20 days for both positive, cTnI positive only, and BNP positive only groups, respectively. Abbreviations: cTnI, cardiac troponin I; BNP, B-type natriuretic peptide.

The diagnosis at the time of admission was categorized into organ-based major groups. For patients with double elevations (N=105), cardiovascular disease (N=43, 41.0%) was most common, followed by respiratory disease (N=18, 17.1%) and gastrointestinal disease (N=11, 10.5%). The most common diagnosis of a single disease was heart failure (N=16), followed by ACS (N=13), and pneumonia (N=12). For patients with only cTnI elevation (N=74), cardiovascular disease (N=30, 40.5%) was the most common disease, followed by neurological (N=20, 27.0%), respiratory (N=7, 9.5%), and gastrointestinal diseases (N=7, 9.5%). The most common diagnosis of a single disease was ACS (N=20), followed by cerebral infarction (N=6), and stable angina (N=5). For patients with only BNP elevation (N=231), cardiovascular disease (N=48, 20.8%) was the most common affliction, followed by gastrointestinal (N=46, 19.9%), respiratory (N=42, 18.2%), neurological (N=39, 16.9%), and renal diseases (N=27, 11.7%). The most common diagnosis as a single disease was pneumonia (N=29), followed by heart failure (N=19), cerebral infarction (N=19), chronic kidney disease (N=14), and cholangitis (N=10).

2) Patients with marginally increased cardiac troponin

Among the 253 patients with elevated cTnI (sole cTnI elevation and concurrent BNP elevations together), 212 patients (83.8%) showed low-level positivity. In this subgroup, patients with elevations in both markers were also hospitalized more at the ED (76.7% versus 59.4%, P=0.010) and had longer length of hospital stay after admission (10 [5-21] versus 6 [4-15] days, P=0.019) than those with only cTnI elevation.

DISCUSSION

In this study, we determined whether simultaneous measurements of BNP and cTnI were relevant at the ED where time is critical and enough data about patients is unavailable in many cases. We found that the hospital course of the patients with elevations in both biomarkers appeared to be different compared to those with elevations in levels of only cTnI or BNP. The multiple marker approach can provide additional information regarding the simultaneous elevation of the marker levels, other than assisting in the diagnosis/exclusion of ACS in cases of possible heart failure.

The ED physician might have considered the clinical status of patients positive for both the markers to be more serious, which might have increased the admission rate (Table 1 and Fig. 2). The length of hospital stay after admission was longer in patients with double elevations compared to those with cTnI only elevation, but similar to those with BNP only elevation. This might be related to chronicity of disease or relatively older mean age (>70 years) in patients with BNP elevation. Among patients with cTnI elevation, certain findings such as higher admission rate and longer length of hospital stay were still observed when the patients with low-level positive cTnI (0.03-0.40 ng/mL) were only included in the analysis. This level of elevation can be observed in various clinical situations, and the patients are relatively heterogeneous in terms of their afflictions compared to those with overtly positive cTnI levels.

POC testing of cTnI and BNP may assist the ED physicians in prompt triage, accurate diagnosis, and management of patients due to rapid delivery of the results within 15-20 minutes with comparable sensitivity and specificity [9,10,16]. POC testing of cTn1 has also resulted in a substantial lowering of charges per patient admission in a metropolitan medical center of the USA, although in a small number of patient [10,17]. In this study, about one of five patients (22.3%, 596/2,674) who visited the ED of the university hospital and underwent POC testing showed positive cTnI and/or BNP result. Our patients might represent a mixed population with variable clinical situations, although each hospital may be identified by specific patient characteristics. The positive rates for cTn or BNP differ according to the patient population and cutoff used [13,16]. Troponin (cutoffs 1.0 and 0.1 ∞g/L for cTnI and cTnT, respectively) was positive in 6.2% patients with acute decompensated heart failure, and BNP (cutoff 80 pg/mL) was positive in 10.6% patients with ST-segment elevation myocardial infarction in previous studies [18,19].

This study has several limitations. First, we did not review the medical records of the patients who were negative for both the markers in detail. Therefore, the admission rates of the cTnI-negative and the BNP-negative group could not be calculated. In addition, other factors affecting admission rate and hospitalization period were not assessed. Second, this study was retrospective in design. Third, positive BNP results could be due to decreased renal function such as chronic kidney disease. Fourth, we could not compare the results of the central laboratory with those of POC testing.

In conclusion, we observed that patients with concurrent elevations of BNP and cTnI may be associated with inferior clinical outcome. Combined and sensitive testing of cTnI and BNP would provide additional information for patients with suspected ACS and aid in the identification of heart failure. In addition, it would assist in excluding ACS in patients with suspected heart failure, which can be helpful for management decisions.

Article information

Journal of Laboratory Medicine and Quality Assurance.Jun 30, 2017; 39(2): 83-89.
Published online 2017-06-30. doi:  10.15263/jlmqa.2017.39.2.83
1Department of Laboratory Medicine, Veterans Health Service Medical Center, Seoul, Korea
1중앙보훈병원 진단검사의학과
2Department of Laboratory Medicine, Konkuk University School of Medicine, Seoul, Korea
2건국대학교 의학전문대학원 진단검사의학교실
3Green Cross Laboratories, Yongin, Korea
3녹십자의료재단
Yeo-Min Yun Department of Laboratory Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea Tel: +82-2-2030-5582 Fax: +82-2-2030-5587 E-mail: ymyun@kuh.ac.kr
Received December 1, 2016; Accepted April 10, 2017.
Articles from Journal of Laboratory Medicine and Quality Assurance are provided here courtesy of Journal of Laboratory Medicine and Quality Assurance

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Figure 1

1)Comparison of double marker elevation with single marker elevation
Distribution of patients based on the positivity for two cardiac markers. Five hundred and ninety-six patients (22.3%) had elevated BNP and/or cTnI concentrations. The 99th percentile of cardiac troponin I is 0.02 ng/mL, and hence, values ≥0.03 ng/mL were considered to be positive. The cutoff for BNP is 100 pg/mL. Abbreviations: BNP, B-type natriuretic peptide; cTnI, cardiac troponin I.

Figure 2

Table 1

Clinical and laboratory characteristics in patients with cardiac troponin I and/or B-type natriuretic peptide elevation

Variable Patients with double elevations (N=135) Patients with only cTnI elevation (N=118) Patients with only BNP elevation (N=343)



cTnI (+)/BNP (+) * cTnI (+)/BNP (-) * P-value cTnI (-)/BNP (+) * P-value
Age (yr) 74.2±11.2 61.9±16.8 <0.001 72.4±13.1 0.145
Length of ED stay (min) 228 (151–345) 200 (103-326) 0.112 263 (185–345) 0.026
Admission rate after ED visit (%) 78.5 (106/135) 62.7 (74/118) 0.006 67.3 (231/343) 0.016
Length of hospital stay after admission (day) 11 (5–19) 6 (3–13) 0.001 10 (5–20) 0.761
Readmission rate within 3 months of discharge (%) 17.9 (19/106) 10.8 (8/74) 0.188 16.5 (38/231) 0.737
Mortality rate within 1 year (%) 17.0 (19/112) 17.9 (14/78) 0.860 12.7 (31/245) 0.276
cTnI (ng/mL, half-life about 2 hr) 0.07 (0.04–0.18) 0.05 (0.03–0.19) 0.429 0.01 (0.01–0.01) -
BNP (pg/mL, half-life 20 min) 430 (228–727) 23 (9–46) - 194 (140–322) <0.001

Values are presented as mean±SD, median (interquartile range), or percentage (number of patients/total patients included in the analysis).

Abbreviations: cTnI, cardiac troponin I; BNP, B-type natriuretic peptide; ED, emergency department.