Study Design

Prospective study designs included two randomized controlled trials (RCT)^97,102 and nine cohort studies.^{92,98,106,116-121} The remaining papers (n=40) used a cross-sectional design. The selected articles were published between 2001 and 2011 and were conducted in a wide range of regions: nine in North America,^{72,82,83,90,101,105,107,117,120} twenty-two in Europe^{74,79,85,87,88,94,96,100,102-104,106,109-115,118,119,121} two in Asia,^86,95 one in South America,⁷⁸ two in Australia,^89,97 and one in New Zealand.¹⁰⁸ Thirteen papers were conducted in multinational sites^{3,73,75-77,80,81,84,91-93,98,99} and one was unclear as to region of conduct.¹¹⁶

Population Characteristics

Most articles, with the exception of ten,^{74,84,87,90,91,96,109,115,119,120} provided diagnostic information on the overall study sample. Some papers provided diagnostic information on populations grouped according to age,^{73,74,85,89,101,111,113,119} sex,^73,74 and ethnicity.⁷³

Some papers presented diagnostic information according to body mass index (BMI) status,^91,101,102 diabetes status,⁸⁴ previous history of heart failure (HF),^72,89,96 permanent/paroxysmal atrial fibrillation (AF),⁹² renal function/estimated glomerular filtration rate (eGFR),^{101,109,113,114,120} history of hypertension or blood pressure elevation on admission,⁹⁹ and left ventricular ejection fraction (LVEF).¹¹⁶ Three papers included information on HF populations.^76,100,102

In all papers, study patients presented to emergency departments with shortness of breath and were 18 years of age and older. Seventeen articles had a patient population with mean or median ages from 60 to 69 years old^{72,73,75-77,79-81,83,84,91,93,99,104,118,121,122} and 14^{74,78,87,89,95-97,101,102,106-109,114} had populations with mean or median age ranges between 70 and 79. Four studies had a mean or median patient population over 80 years of age^{85,94,105,112} and ten did not report on age of study population.^{3,82,86,88,90,98,116,117,119,120} Six articles reported ages in the following ranges: 65 to 100,¹¹¹ 43 to 90,¹¹³ 67 to 82,¹²³ 58 to 82,¹¹⁰ 68 to 82,¹⁰⁰ and 30 to 95 years.¹⁰³

The percentage of males enrolled in each study ranged from 5.6 percent⁸⁴ to 100 percent⁷² (mean=66.2%; median=66.2%). Sample size populations (including subpopulations) ranged from 9⁸⁹ to 1,614³ (mean=404, median=251). The prevalence of HF in the study populations ranged from 8.3 percent¹⁰⁰ to 84 percent⁹⁶ (mean=45.1%; median=46.6%).

Component Articles

Of the 51 selected papers, 11 used data from the Breathing Not Properly Multinational Study,^{73,75-77,80,81,84,91-93,99} three used data from the B-type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study,^96,102,106 one from the Biomarkers in Acute Heart Failure (BACH) study,³ and one from the BNP in Shortness of Breath study.⁹⁷ One article used data from the Heart Failure and Audicor technology for Rapid Diagnosis and Initial Treatment (HEARD-IT) study,⁹⁸ and one was from the epidemiological study of acute dyspnea in elderly patients (EPIDASA) study.⁸⁵ One set of authors published results on the same data sets^114,119 and the remaining articles (n=31) were independent papers, publishing results on unique data sets.

Assays Tests

Seven articles used the Abbott AxSYM^® B-Type Natriuretic Peptide (BNP) Microparticle Enzyme Immunoassay (MEIA)),^{95,97,98,100,106,110,115} five used the TRIAGE-B-Type Natriuretic Peptide (BNP) test for the Beckman Coulter Immunoassay Systems,^{3,103,116,118,121} two used the I-STAT BNP test,^101,107 two used the ADVIA-Centaur^® BNP Assay, Bayer Diagnostics ACS:180^® BNP Assay,^98,113 and two used the ADVIA-Centaur^® B-Type Natriuretic Peptide (BNP) Assay.^88,98 The remaining papers (n=35) used the TRIAGE-B-Type Natriuretic Peptide (BNP) test.

Diagnosis of Heart Failure in Papers

The majority of articles (n=45) based the diagnostic reference standard on clinical judgment.^{3,72-81,83-85,87,89-99,101-104,106-109,111-121} Of these 45 articles, most (n=34) had a reference standard agreed upon by at least two physicians (mostly cardiologists), ten based the final diagnosis on the opinion of a single cardiologist or other type of clinician,^{72,78,89,96,102,107,109,118-120} and one article did not indicate this information.¹²¹ The adjudication physicians each arrived at a diagnosis of HF based on their interpretation of all available clinical data; this often included echocardiography results. One article¹⁰⁶ included BNP in the data used for adjudication. Of the 45 papers using clinical judgment to make the final diagnosis, the Framingham criteria were used in 15, and the National Health and Nutrition Examination Survey (NHANES) was used in 10.

Of the remaining articles (n=6), three based the final diagnosis of HF both on clinical judgment and results of echocardiography,^82,88,100 one based it on echocardiography results alone,⁸⁶ one reported that the definitive diagnosis was based on the Framingham criteria,¹¹⁰ and one reported that the HF status was based on discharge diagnosis.¹⁰⁵

Diagnostic Properties in BNP

The 51 papers evaluating BNP in the emergency department used several cutpoints ranging from 12.5⁸⁶ to 983.5⁸⁶ pg/mL or ng/L (mean=213.1; median=162). One study measured BNP in pmol/L and had cutpoints ranging from 20 to 100.¹⁰⁸ These were converted to pg/mL for analysis. Reported sensitivities ranged from 36 percent⁹² to 100 percent^{74,78,86,89,113} (mean=82.4 percent; median=86 percent), specificities from 14 percent⁷⁶ to 99 percent⁹⁶ (mean=75.4 percent; median=79.5%), and areas under the curve (AUC) of 0.08⁹² to 0.99^78,82 (mean=0.84; median=0.89). Of the 51 papers looking at BNP, 14 also looked at NT-proBNP.^88,108-120 Appendix H Tables H-1 and H-2 present summary tables of these studies.

The majority of papers reported on the Triage BNP Point-of-Care test. Two papers reported on the Triage BNP test licensed to Beckman Coulter for use on their laboratory instruments.^3,103 Four papers reported using the Abbott AxSYM,^{97,100,101,110} and one reported using the ADVIA-Centaur system.⁸⁸ Gorissen et al.¹¹³ reported on two systems (ADVIA-Centaur and Triage).

Data were extracted, 2x2 tables prepared, and forest plots of sensitivities, specificities, positive and negative likelihood ratios (LRs), diagnostic odds ratios (DORs), and summary receiver operator characteristic (ROC) curves are presented (see Appendix H Figures H-1 to H-12). Three cutpoints were selected: lowest presented, manufacturers' suggested, and the optimal cutpoint as chosen by the authors.

If the lowest cutpoint presented by the authors is chosen, all papers except four^{111,113,119,120} return sensitivities greater than 90 percent (summary estimate 95 percent, (95% confidence interval (CI) 93 to 97 percent)). Negative LRs (LR^-) were all less than 0.20 for this group. Overall, specificity was lower and much more variable, ranging from 27 to 88 percent (summary estimate 67 percent (95% CI, 58 to 75 percent)).

Among papers that reported a sensitivity less than 90 percent, Ray et al.¹¹¹ and Chevenier-Gobeaux et al.¹¹⁹ enrolled patients older than 65 years. Both papers used higher cutpoints than most other papers (Ray: 250 pg/mL; Chevenier-Gobeaux: 270 pg/mL 65-84 years, and 290 pg/mL >85 years). deFilippi et al.¹²⁰ enrolled a population with a high prevalence (47 percent) of subjects with eGFR <60 mL/min/1.73 m². Gorrison et al.¹¹³ reported using the ADVIA-Centaur and Triage assay systems. They also selected a high cutpoint (225 pg/mL) and report a sensitivity of 65 percent and 73 percent, below all other papers.

Using package inserts, 501(k) submission forms, and product brochures, we determined the manufacturers' recommended cutpoints. In all cases the manufacturer suggested a cutpoint of 100 pg/mL to rule out the diagnosis of HF. Twenty-one papers reported for this cutpoint. Sensitivities ranged from 86 to 100 percent (summary estimate 95 percent (95% CI, 93 to 96%)), and specificities ranged from 31 to 97 percent (summary estimate 66 percent (95% CI, 56 to 74 percent)).^{3,74,79,81-83,85,86,88,89,93,95-97,101,104,107,108,110,112,114}

Twenty-eight papers^{3,74,77-79,81-83,85,86,89,91,93-98,100,104,108,110-114,119,120} examined an optimal cutpoint. The majority (n=19) of the studies determined a cutpoint that maximized accuracy, either using an ROC curve or by examining several arbitrary cutpoints^{74,77-79,81-83,85,86,94,96,97,108,110-113,119,120} Three studies maximized sensitivity,^89,93,104 three others used the manufacturers' suggested cutpoint or other accepted threshold^3,91,114 and one study used multiple logistic regression,⁹⁵ one set the sensitivity at 90 percent and determined specificity,¹⁰⁰ and one set the sensitivity at 96 percent in all subgroups and determined specificity.⁹⁸ Sensitivities ranged from 65 percent to 100 percent (summary estimate 91 percent (95% CI, 88 to 94 percent)), specificities ranged from 34 percent to 97 percent (summary estimate 80 percent (95% CI, 74 to 85 percent)). Using the optimal cutpoint resulted in a higher overall estimate of the positive LR (LR⁺ (4.61, 95% CI, 3.49 to 6.09) compared to either the lowest cutpoint (2.85 (95% CI, 2.23 to 3.65)), or the manufacturer cutpoint (2.76 (95% CI, 2.12 to 3.59)). The LR^- was not significantly different (p>0.05).

Choosing the lowest, manufacturer, or the optimal cutpoint had little effect on the diagnostic performance of the test. The test displayed high sensitivity and a high LR^-, but a low specificity and LR⁺.

Age

Eight articles^{73,74,85,89,101,111,113,119} examined the relationship between age and BNP. In all cases, increasing age was associated with an increase in BNP concentration, but the correlation of age with the diagnostic performance of the test was not clear in the papers.

Six papers examined the effect of age on the AUC (Table 1).^{73,74,85,89,113,119}

Table 1

Effect of age on AUC for BNP.

Four papers^{73,101,111,119} examined different decision cutpoints based upon age, each using different reasoning and criteria (Table 2). Maisel et al.⁷³ suggested cutpoints no greater than 100 pg/mL for both age groups, above and below 70 years of age. These decision points maximized sensitivity, with specificity being the second concern. Their reasoning was that a false negative result was less desirable than a false positive in terms of cost to the patient.

Table 2

Effect of age on diagnostic performance of BNP.

Rogers et al.¹⁰¹ using the manufacturers' suggested cutpoint of 100 pg/mL, established the sensitivity of the entire cohort at 91 percent. To achieve 91 percent sensitivity in those 75 years of age and older, the decision point was set at 184 pg/mL. The specificity at this point was 54 percent.

Chenevier-Gobeaux¹¹⁹ examined the very elderly, 85 years of age and older, compared with those aged 65 to 84. For the younger group, the optimal cutpoint was 270 pg/mL (sensitivity 73%, specificity 83%), whereas for the very elderly the optimal cutpoint was 290 pg/mL (sensitivity 80%, specificity 69%).

For those aged 65 and older, Ray et al.¹¹¹ established an optimal cutpoint of 250 pg/mL (sensitivity 73%, specificity 91%). In an earlier paper,⁸⁵ these authors also established an optimal cutpoint of 250 pg/mL (sensitivity 78%, specificity 90%). It is not clear if these publications used independent study populations.

Gorissen et al.¹¹³ examined two different BNP assays and divided their population into three age groups. For the Triage assay, the optimal cutpoint for those less than 65 years was 91 pg/mL (sensitivity 55%, specificity 100%), for those 65 to 75 years of age it was 260 pg/mL (sensitivity 83%, specificity 82%), and for those greater than 75 years the optimal cutpoint was 309 mg/mL (sensitivity 71%, specificity 68%). Similarly, for the Siemens Centaur assay the cutpoints were 91 mg/mL (sensitivity 55%, specificity 100%), 188 pg/mL (sensitivity 83%, specificity 73%), and 247 pg/mL (sensitivity 77%, specificity 68%) respectively.

All authors reported that the optimal BNP threshold for diagnosis of HF increases with age, but there is no consensus on how to set the threshold.

Sex

Two papers examined sex and BNP^73,74 (Table 3). Maisel et al.⁷³ reported that the difference in BNP concentrations between men and women was not significant. Knudson et al.⁷⁴ noted differences in sensitivity between males and females using 100 pg/mL as the decision point (males: sensitivity 94.3%, specificity 54.9%; females: sensitivity 90.0%, specificity 55.2%).

Table 3

Effect of sex on AUC for BNP.

Ethnicity

One study examined the effect of ethnicity on the diagnostic properties of BNP. Maisel et al.⁷³ reported that the prevalence of HF in their population was significantly greater among whites than among African Americans. Similarly, the concentration of BNP in the white population was significantly greater than in the African American population (200 vs. 117 pg/mL, p<0.001). The AUC is shown in Table 4.

Table 4

Effect of ethnicity on AUC for BNP.

Obesity/Body Mass Index

Three papers^91,101,102 examined the effect of obesity on the diagnostic properties of BNP. All three showed that increasing BMI was associated with reduced BNP concentrations. This was true if BMI and BNP were examined in the whole population,^101,102 or if the population was examined in two groups: those with and without HF.⁹¹

Daniels et al.⁹¹ examined the diagnostic properties using a fixed decision point of 100 pg/mL. The sensitivity decreased, but the specificity increased as the BMI increased. In this study the decision points to achieve 90 percent sensitivity was 170 pg/mL for BMI less than 25 kg/m², 110 pg/mL for BMI 25 to 35 kg/m², and 54 pg/mL for BMI greater than 35 kg/m². Specificity was greater than 70 percent in all three subgroups. Rogers et al.¹⁰¹ also adjusted the decision point of the BMI greater than 35 kg/m² group to achieve the same sensitivity (91%) as the entire cohort (100 pg/mL). This decision point (25 pg/mL) resulted in a reduced specificity. Noveanu et al.¹⁰² examined the diagnostic properties at two decision points, 100 and 500 pg/mL. Table 5 displays the diagnostic properties of these papers.

Table 5

Effect of body mass index on diagnostic performance of BNP.

Renal Function

Five papers^{101,109,113,114,120} examined the relationship between renal function and the diagnostic properties of BNP. Four^{109,113,114,120} examined eGFR (Table 6) and one¹⁰¹ examined serum creatinine concentration. Three papers^109,114,120 optimized the decision point based on eGFR, two^109,114 maximized sensitivity, and one¹²⁰ maximized accuracy.

Table 6

Effect of renal function on diagnostic performance of BNP.

The BNP concentration was inversely related to renal function: as the eGFR decreased or creatinine concentration increased, the BNP concentration increased.

Using the recommended cutpoint of 100 pg/mL, Rogers et al.¹⁰¹ reported a sensitivity of 100 percent and a specificity of 30 percent for those subjects with serum creatinine ≥2 mg/dL. They then adjusted the decision point for those subjects with serum creatinine ≥2 mg/dL to equal the sensitivity of the entire cohort using the recommended decision point of 100 pg/mL (sensitivity 91%, specificity 54%). This resulted in a cutpoint of 449 pg/mL (specificity 78%).

While these authors recognized that sex, ethnicity, obesity, and renal function have significant effects upon concentration of BNP and potentially on the diagnostic performance of BNP in the diagnosis of HF in the emergency department, all also recognized the difficulty in establishing multiple decision points.

Diabetes

One study⁸⁴ examined the effect of diabetes mellitus on the use of BNP for the diagnosis of HF. This study reported a nonsignificant difference in the AUC of 0.888 (95% CI, 0.860 to 0.912) for nondiabetics versus 0.878 (95% CI, 0.837 to 0.913) for diabetics.

Study Design

Eleven papers were prospective cohort studies,^{116-122,135,136,139,143} one was case-control¹³¹ and in two papers, the study design could not be determined.^132,141 The remaining papers (n=25) used a cross-sectional design. The selected articles were published between 2003 and 2011. Thirteen were conducted in North America,^{1,117,120,125,127,128,130,132-134,136,138,139} 18 in Europe,^{26,88,109-115,118,119,121,124,129,131,135,142,143} one in New Zealand,¹⁰⁸ two in Asia,^122,137 and one in Australia.¹⁴¹ Two papers were conducted in multinational sites^2,126 and two were unclear as to region of conduct.^116,140

Population Characteristics

Most papers, with the exception of ten,^{109,119,120,126,127,130,137,139,140,142} provided diagnostic information on the overall study sample presenting to the emergency department with dyspnea. Some papers provided diagnostic information on populations grouped according to age,^{2,113,119,122,129,133} sex,¹²⁷ and ethnicity.¹²⁷ Some presented diagnostic information according to BMI status,¹²⁶ renal function,^113,130 chronic obstructive pulmonary disease status (COPD)/HF history,¹²⁸ clinical certainty/uncertainty,¹³⁹ normal/abnormal chest radiograph,¹³⁴ with/without diabetes mellitus,¹⁴⁰ and NT-proBNP versus usual care.¹²⁵ Papers examined groups by eGFR readings,^{109,113,114,120} LVEF readings,¹¹⁶ and red cell distribution width.¹³⁷

In all papers, patients presented to emergency department with shortness of breath and were 18 years of age and over. Twelve papers had a patient population with mean or median ages from 60 to 69 years^{2,26,118,120-122,127,128,134,137,139,142} and 19 had mean or median ages between 70 and 79 years.^{1,88,108-110,113-115,124-126,130-133,136,138,141,143} Five had mean populations aged 80 and over^{111,112,119,129,135} and one had a population with a mean age under 60 years.¹¹⁷ Two papers did not report age.^116,140

The percentage of males enrolled in each study ranged from 39.0 percent¹¹⁴ to 93.2 percent¹¹⁰ (mean=53.3%; median=51.0%). Sample size populations ranged from 68¹⁴¹ to 1,256² (mean=377, median=378). The prevalence of HF in the study populations ranged from 8.3 percent¹⁴⁴ to 63.5 percent¹²⁸ (mean=37.9%, median=34.9%).

Component Papers

Of the 39 selected papers, ten were from the N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study,^{1,2,127,128,130,132-134,139,140} two were from the Mannheim NT-proBNP Study (MANPRO),^26,142 one was from the International Collaborative of NT-proBNP (ICON) data set,¹²⁶ one was from the BACH study,¹²⁵ one was from the Improved Management of Patients with Congestive Heart Failure (IMPROVE CHF) trial,¹³⁶ and one came from the epidemiological study of acute respiratory failure in elderly patients (EPIDASA) study.¹¹¹ The remaining (n=23) were independent papers, publishing results on unique data sets.

Assays Tests

The majority of papers (n=35) used the ELECSYS^® proBNP Immunoassay. Of the remaining papers, three used the DIMENSION-EXLTm N-terminal Pro-Brain Natriuretic Peptide (NTP) Flex^® Reagent Cartridge (RF623)^26,142,145 and, in the case of one study, the assay used was not stated.¹⁴³

Diagnosis of Heart Failure in Papers

The majority of papers (n=35) based the diagnostic reference standard on clinical judgment. Most of these (n=31) had a reference standard agreed upon by at least two physicians (mostly cardiologists) and five based the final diagnosis on the opinion of a single cardiologist or other type of clinician.^{1,26,110,118,141} One study did not indicate the number or qualifications of the adjudicators.¹²² The adjudication physicians each arrived at a diagnosis of HF based on their interpretation of all available clinical data; this often included echocardiography results. Of the papers judging final diagnosis using clinical judgment, (n=34) three used the Framingham,^110,136,143 two used the Boston Criteria,^135,143 one used the European Society of Cardiology guideline,¹⁴² and one used the NHANES.¹³⁶

Of the remaining papers (n=2), one based the final diagnosis of HF both on clinical judgment and echocardiography results¹³⁷ and one based it solely on the European Society of Cardiology guidelines.¹³¹

Diagnostic Properties in NT-proBNP

The 39 papers evaluating NT-proBNP in the emergency department used several cutpoints ranging from 100²⁶ to 6,550¹⁰⁹ pg/mL or ng/L. Reported sensitivities ranged from 53 percent¹¹² to 100 percent^{88,112,114,127} (mean=85.1%; median=88%), specificities from 5 percent¹¹² to 100 percent,¹¹³ (mean=70.9% ; median=73.2%), LR⁺ from 1.05¹¹² to 115.03,⁸⁸ LR^- from 0.02^88,114 to 0.35,¹¹⁹ and AUC of 0.6¹¹⁶ to 0.99² (mean=0.88; median=0.89). Most of the papers (n=32) looked at NT-proBNP alone, with the exception of 15 that examined both BNP and NT-proBNP.^88,108-121 Appendix H Table H-4 presents summary data for those papers that examined NT-proBNP.

Of the 19 papers with diagnostic performance data,^{2,26,88,108,110-115,119,122,124,129,131,135,138,141,143} 17 reported on data from the Roche NT-proBNP assay system. One²⁶ used the Dimension EXL system, and one¹⁴³ used the Roche Cardiac Reader point-of-care test.

Data were extracted, 2×2 tables prepared, and forest plots of sensitivities, specificities, LR⁺ and LR^-, DOR, and summary ROC curves are presented (Appendix H Figures H-13 to H-24). Two cutpoints were selected: lowest presented, and the optimal cutpoint, as chosen by the authors to examine in greater detail.

The diagnostic performance was examined using the lowest cutpoint presented by each author in order to maximize the test sensitivity.

Nineteen papers used an optimal cutpoint in their analysis.^{2,26,88,108,110-115,119,122,124,129,131,135,138,141,143} Eleven papers used a cutpoint to maximize accuracy, either using an ROC curve or with several arbitrary cutpoints. These points ranged from 825 to 2,000 pg/mL. Two studies^122,129 used two decision points; one at 300 or 1,200 pg/mL, respectively, to maximize sensitivity, and one at 900 or 4,500 pg/mL, respectively, to maximize specificity. Two papers chose 300 pg/mL, one²⁶ to maximize sensitivity, and one¹¹⁴ chose this value as the “accepted” threshold. One study¹⁴³ used the Roche Cardiac Reader point-of-care assay and chose the cutpoint of 1,000 pg/mL but did not provide a reason.

Age

Januzzi et al.² determined two cutpoints to separate the population into three age groups. For those less than 50 years of age, 450 pg/mL was determined as the best cutpoint to rule out HF (maximum sensitivity). For those 50 to 74 years of age, they chose 900 pg/mL as the best combination of sensitivity and specificity to maximize test accuracy, and for those 75 years of age or older, 1,800 pg/mL provided the maximum specificity in order to rule in HF. Two other papers^138,141 adopted this protocol as the optimal cutpoints. Using this approach did not appear to result in significantly improved diagnostic performance compared with the overall estimate. Table 7 shows the diagnostic performance of these papers compared to the overall estimate of the entire group of NT-proBNP papers.

Table 7

Effect of age optimized cutpoints on diagnostic performance of NT-proBNP.

Compared to the lowest cutpoint, the optimal cutpoint displayed a higher overall estimate of specificity and LR⁺, but was not significantly different in other performance indicators. These data are presented in Table 8.

Table 8

Effect of cutpoint on diagnostic performance of NT-proBNP.

One study¹²² used two cutpoints (900 pg/mL >50 years and 450 pg/mL <50 years) for rule in, and a single cutpoint (300 pg/mL) for rule out.

Six papers^{2,113,119,122,129,133} reported on the effect of age on the performance of NT-proBNP in the diagnosis of HF.

Berdagué et al.¹²⁹ examined subjects 70 years of age and older, and proposed the use of two decision points for this population: a lower decision point of 1,200 pg/mL to maximize sensitivity (97%) and an upper point of 4,500 pg/mL to maximize specificity (86%). Patients with values in the intermediate “gray” zone required further investigation. A single decision point of 2,000 pg/mL resulted in a test accuracy of 80 percent, deemed unacceptable by the authors of this report.

Januzzi et al.¹³³ examined decision points based on age to optimize rule in, the single cutpoint proposed by the manufacturer, as well as independently generated decision points to evaluate rule out capabilities of the test (Table 9). Januzzi et al.² used data from the ICON study, an international collaboration that includes data from the PRIDE study,¹³³ which reported separate, selected decision cutpoints that emphasized sensitivity for younger patients and specificity for older ones. They proposed three decision points for age groups under 50, 50 to 75, and older than 75 years to rule in the diagnosis and a single point to rule out. Shaikh et al.¹²² optimized rule-in cutpoints based on age <50 and >50, but used a single rule-out cutpoint regardless of age. Gorrison et al.¹¹³ also suggested that the decision points be increased as the age of the patient increases. Chevenier-Gobeaux et al.¹¹⁹ examined the very elderly (≥85 years of age) and proposed distinct decision points (2,800 pg/mL vs. 1,700 pg/mL) for those over and under 85 years of age (Table 9).

Table 9

Effect of age on diagnostic performance of NT-proBNP.

Sex and Ethnicity

Krauser et al.¹²⁷ examined the influence of ethnicity and sex on the diagnostic properties of NT-proBNP. They reported that the AUC was not different for men versus women or for African Americans versus non-African Americans. There was no difference in the median NT-proBNP concentration between men and women. Similarly, there was no difference in the median concentration between African Americans and non-African Americans.

Obesity/Body Mass Index

A single paper¹²⁶ examined the effect of obesity and BMI on NT-proBNP performance (Table 10). Using age-specific decision points previously identified, this substudy of the ICON study divided the population into three BMI groups and then calculated the LR⁺ for each group. Using the overall rule out decision point, they calculated LR^-.

Table 10

Effect of body mass index on diagnostic performance of NT-proBNP.

They commented that the age-adjusted decision points performed well over a wide variety of BMI. Despite lower sensitivity at the high range of BMI, the predictive values were unchanged.

Renal Function

Two papers^113,130 examined the relationship between renal function, expressed as eGFR, and NT-proBNP for the diagnosis of HF (Table 11). Both papers noted an inverse relationship between renal function and NT-proBNP concentration. The relationship was less robust among those with HF than those without. Anwaruddin et al.¹³⁰ in a substudy of the PRIDE cohort, used the age-adjusted decision points from the main study to determine diagnostic parameters. Gorrison et al.¹¹³ used the ROC curve to establish the optimal decision points.

Table 11

Effect of renal function on diagnostic performance of NT-proBNP.

BNP

The QUADAS-2¹⁴⁶ was used to assess quality in four key domains: patient selection, index test(s), reference standard, and flow and timing. The questions in each domain are rated in terms of risk of bias (low, high, unclear) and concerns regarding applicability (low, high, unclear), with associated signaling questions to help with bias and applicability judgments (Figures 3 and 4, and Appendix H Table H-5).

Figure 3

Proportion (%) of diagnostic studies using BNP with low, high, or unclear concerns regarding risk of bias in emergency department.

Figure 4

Proportion (%) of diagnostic studies using BNP with low, high, or unclear concerns regarding applicability in emergency department.

The potential for bias in the domain of patient selection was assessed on the basis of the enrollment of the study sample (consecutive, random, or convenience), the avoidance of case-control design, and the avoidance of inappropriate patient exclusions. For this domain, 25 percent of papers (n=13) were rated as low risk for bias and 20 percent (n=10) were rated as high risk. The remaining papers (n=28; 55%) were rated as unclear as to risk of bias. Papers were assessed as to patient population applicability to those targeted by the review question in terms of severity of the target condition, demographic features, presence of differential diagnosis or comorbid conditions, and setting of the study. Overall, 33 percent (n=17) of papers were assessed as high risk of bias for concerns about applicability on this domain and 57 percent (n=29) were rated as low on concern. The remaining 10 percent (n=5) were deemed unclear on the domain of applicability for patient selection.

The potential for bias in the domain of the index test was assessed according to whether results were interpreted without knowledge of the results of the reference standard and whether a prespecified threshold was used for BNP cutpoints. Seventy-one percent (n=36) of papers were rated as high risk, 20 percent were rated as low risk (n=10), and 9 percent were rated as unclear (n=5) on this domain. Papers were assessed on concerns of applicability on the basis of whether the index test methods varied from those specified in the review questions. Concerns about applicability on this domain were assessed as low for 76 percent (n=39) of papers, as high for 22 percent (n=11), and as unclear for 2 percent (n=1).

The potential for bias in the domain of the reference standard (i.e., the criteria used to confirm a diagnosis of HF) was judged on the basis of whether the reference standard was likely to correctly classify the target condition and whether the results were interpreted with knowledge of the BNP marker results. Papers were rated as low risk for 94 percent (n=48), as high risk for 4 percent (n=2), and as unclear for 2 percent (n=1). Concerns about applicability were assessed as to whether the target condition, as defined by the reference standard, differed from the target condition specified in the review question. Seventy-eight percent (n=40) of papers were assessed as low and 22 percent (n=11) were assessed as high on this domain.

The potential for bias in the domain of flow and timing was assessed on the basis of inappropriate intervals between index test and reference standard, standardized administration of reference standard among patients, and equal inclusion of patients in the analysis. Papers were assessed as low risk of bias for 69 percent (n=35), as high for 20 percent (n=10), and as unclear for 12 percent (n=6) of papers.

NT-proBNP

For papers of diagnostic tests of NT-proBNP (KQ1), QUADAS-2¹⁴⁶ was used to assess quality in four key domains: patient selection, index test(s), reference standard, and flow and timing. The questions in each domain are rated in terms of risk of bias (low, high, unclear) and concerns regarding applicability (low, high, unclear), with associated signaling questions to help with bias and applicability judgments (see Figures 5 and 6, and Appendix H Table H-6).

Figure 5

Proportion (%) of diagnostic studies using NT-ProBNP with low, high, or unclear concerns regarding risk of bias in emergency department.

Figure 6

Proportion (%) of diagnostic studies using NT-ProBNP with low, high, or unclear concerns regarding applicability in emergency department.

The potential for bias in the domain of patient selection was assessed on the basis of enrollment of study sample (consecutive, random, or convenience), the avoidance of a case-control design, and the avoidance of inappropriate patient exclusions. For this domain, 28 percent of papers (n=11) were rated as low risk for bias and 46 percent (n=18) were rated as high risk. The remaining papers (n=10; 26%) were rated as unclear as to risk of bias. Papers were assessed as to patient population applicability to those targeted by the review question in terms of severity of the target condition, demographic features, presence of differential diagnosis or comorbid conditions, and setting of the study. Overall, 33 percent (n=13) of papers were assessed as high for concerns about applicability on this domain, 64 percent (n=25) were rated as low, and five percent (n=2) were rated as unclear on concern.

The potential for bias in the domain of the index test was assessed according to whether results were interpreted without knowledge of the results of the reference standard and whether a prespecified threshold was used for NT-proBNP cutpoints. Slightly more than half of papers (n=22, 57%) were rated as high risk on this domain, 28 percent were rated as low (n=11), and 15 percent were rated as unclear (n=6). Papers were assessed on concerns of applicability on the basis of whether the index test methods varied from those specified in the review questions. Concerns about applicability on this domain were assessed as low for 72 percent (n=28) of papers, as high for 26 percent (n=10), and as unclear for two percent (n=1).

The potential for bias in the domain of the reference standard (i.e., the criteria used to confirm a diagnosis of HF) was judged on the basis of whether the reference standard was likely to correctly classify the target condition and whether the results were interpreted with knowledge of the NT-proBNP results. Sixty-two percent of papers (n=24) were rated as low risk, 23 percent (n=9) were rated as high, and 15 percent (n=6) were rated as unclear. Concerns about applicability were assessed as to whether the target condition, as defined by the reference standard, differed from the target condition specified in the review question. Seventy-two percent (n=28) of papers were assessed as low on this domain, 26 percent (n=10) were assessed as high, and 2 percent were rated as unclear (n=1).

The potential for bias in the domain of flow and timing was assessed on the basis of inappropriate intervals between index test and reference standard, standardized administration of reference standard among patients, and equal inclusion of patients in the analysis. The majority of papers (n=37, 95%) were assessed as low risk of bias on the domain of flow and timing, while 5 percent (n=2) were rated as unclear.

BNP

The SOE estimates were the same for all three cutpoints evaluated. The complete table can be viewed in Appendix H Tables H-7a, H-7b, and H-7c.

Precision

The CIs around the summary estimates of sensitivity and specificity are small (lowest: 0.93 to 0.96; manufacturers' suggested: 0.93 to 0.96; optimal: 0.88 to 0.92). The CIs around specificity are larger (lowest: 0.57 to 0.72; manufacturers' suggested: 0.57 to 0.71; optimal: 0.72 to 0.83). Because the statistical heterogeneity for all summary estimates is large, we rate this domain as imprecise (Table 12).

Table 12

Statistical summary of test performance characteristics based on the manufacturer, optimum, and lowest cutpoints in the emergency department.

NT-proBNP

The SOE estimates were the same for both cutpoints evaluated. The outcome of sensitivity was rated as high for both cutpoints (optimal, lowest). The outcome of specificity wars rated as moderate for both cutpoints due to inconsistency in the value of specificity among studies. Nevertheless, the summary SOE was rated as high. The complete table can be viewed in Appendix H Tables H-9a and H-9b.

Study Design

One study used a prospective cohort design¹⁵¹ and the remaining studies (n=11) used a cross-sectional design. The selected articles were published between 2005 and 2011 and were conducted in a wide range of regions: two in North America,^152,159 eight in Europe,^{148,150,151,153-157} one in Asia,¹⁵⁸ and one paper in which country of origin could not be determined.¹⁴⁹

Population Characteristics

Most studies, with the exception of three,^150,158,159 provided diagnostic information on an overall study sample with dyspnea in a primary care setting. One study provided diagnostic information on populations grouped according to age and sex.¹⁵⁸ Several studies presented diagnostic information according to BMI status,^158,159 renal function,¹⁵⁸ LVEF levels,¹⁵⁸ and left ventricular systolic dysfunction (LVSD) status.^150,155

In all studies, study patients presented to a primary care facility with shortness of breath and were over 18 years of age. Most studies (n=8) had a patient population with mean or median ages from 70 to 79 years old. Three studies had patient populations with means or medians between 60 and 69 years old^155,158,159 and one¹⁶⁰ had a population under 60 years of age.

The percentage of males enrolled in each study ranged from 25 percent¹⁵³ to 100 percent¹⁵⁸ (mean=51.2%; median=50%). Sample size populations ranged from 53¹⁵² to 1,032¹⁵⁸ (mean=346.8; median=357). The prevalence of HF in the study populations ranged from seven percent¹⁵⁸ to 67 percent¹⁴⁸ (mean=41.5 %; median=38.5%).

Component Studies

The majority of papers (n=9) were independent studies, publishing results on unique data sets. One article used data from the study for the evaluation of the clinical applicability of BNP in the diagnosis and management of patients with suspected HF in primary care (PANAMA),¹⁵³ one reported results from the Utrecht Heart Failure Organization - Initial Assessment (UHFO-IA) study¹⁵⁴ and one study recruited patients from the Screening to Prevent Heart Failure (STOP-HF) study.¹⁵⁵

Assays

Ten studies used the TRIAGE-B-Type Natriuretic Peptide (BNP) test,^{148-153,155-157,159} one used the ADVIA-Centaur^® B-Type Natriuretic Peptide (BNP) Assay,¹⁵⁸ and one used the Abbott AxSYM^® B-Type Natriuretic Peptide (BNP) Microparticle Enzyme Immunoassay (MEIA).¹⁵⁴

Diagnosis of Heart Failure

Most studies (n=8) based the diagnostic reference standard solely on clinical judgment.^{148-151,154,157-159} Most of these had a reference standard agreed upon by at least two physicians (mostly cardiologists), with the exception of two papers, which based the final diagnosis on the opinion of a single cardiologist or other type of clinician.^157,159 The adjudication physicians each arrived at a diagnosis of HF based on their interpretation of all available clinical data; this often included echocardiography results. Four of the studies^{148,149,151,153} judging final diagnosis using clinical judgment stated that the Framingham criteria were used to assist in judgment.

Of the remaining studies, two based final diagnosis of HF on echocardiography results alone,¹⁵² and one simply reported that the diagnosis was “based on the Framingham criteria.”¹⁵³ One study did not report the reference standard used.¹⁵⁵

Diagnostic Properties in BNP

The 12 studies evaluating BNP in primary care settings used several cutpoints ranging from 30^148,157 to 500¹⁴⁸ (mean=158; median=100) pg/mL or ng/L, and reported sensitivities from 25 percent¹⁵³ to 97 percent¹⁴⁸ (mean=82.1%; median=83.9%), specificities from 23 percent¹⁵¹ to 92 percent¹⁴⁸ (mean=73.8%; median=80.4%), and AUCs of 0.62¹⁵⁹ to 0.93¹⁵⁸ (mean=0.86; median=0.88). Six studies examined BNP only^154-159 and six focused on both BNP and NT-proBNP.^148-153 See Appendix I Tables I-1 and I-2.

When the appropriate data were available for extraction or calculation, 2×2 tables were prepared and forest plots of sensitivities, specificities, positive and negative LRs, logDOR, and summary ROC curves are presented (Appendix I Figures I-1 to I-9). Three cutpoints were selected: lowest presented, manufacturers' suggested, and the optimal cutpoint as chosen by the authors.

The pooled sensitivity using the optimum cutpoint was 0.82 (95% CI, 0.69 to 0.90). All but a single study by Barrios et al.¹⁵³ which had a sensitivity of 0.25, had specificities greater than 0.80. The low sensitivity of the Barrios study may be due to a predominantly elderly population and high prevalence of diastolic HF. Pooled specificities were, as expected, not as high and gave an overall specificity of 0.64 (95% CI, 0.45 to 0.79). Summary LR⁺ and LR^- and the logDOR were 2.27 (95% CI, 1.43 to 3.62), 0.28 (95% CI, 0.16 to 0.49), and 2.06 (95% CI, 1.27 to 2.84), respectively. Pooling using the lowest cutpoint produced a slightly higher sensitivity of 0.89 (95% CI, 0.77 to 0.95) and a corresponding lower specificity of 0.54 (95% CI, 0.41 to 0.66). The LR⁺ and LR^- and logDOR gave similar results: 1.94 (95% CI, 1.47 to 2.57), 0.20 (95% CI, 0.09 to 0.44), and 2.27 (95% CI, 1.32 to 3.22), respectively.

Studies were pooled based on the manufacturers' suggested cutpoint because this is likely the most commonly used cutpoint in clinical use. Studies were included if the cutpoint used was within 5 pg/mL of 100. Eight studies were included in the pooled statistics, as they all used the Triage BNP assay. Other manufacturers were not included. The overall sensitivity of 0.76 (95% CI, 0.59 to 0.87) based on the manufacturers' cutpoint was slightly lower than that for the optimal cutpoint. Corresponding specificity was increased slightly to 0.71 (95% CI, 0.52 to 0.85). The LR⁺ and LR^- and logDOR gave results similar to the optimal cutpoint, 2.63 (95% CI, 1.59 to 4.36), 0.34 (95% CI, 0.20 to 0.57), and 2.08 (95% CI, 1.24 to 2.92), respectively.

Summary ROC curves were also developed. As with the summary plots, the ROC curves were developed based on the optimum, lowest, and manufacturers' cutpoints and are presented in Appendix I Figures I-10 to I-12. The AUCs were 0.81 (95% CI, 0.77 to 0.84) for the optimum cutpoint, 0.76 (95% CI, 0.72 to 0.80) for the lowest cutpoint, and 0.80 (95% CI, 0.76 to 0.83) for the manufacturers' suggested cutpoint.

Age

A single study examined the association of age with BNP. Park et al.¹⁵⁸ compared the performance of BNP for patients above and below 65 years of age for the identification of LVEF or advanced diastolic dysfunction (DD). For patients 65 years of age and greater, using a cutpoint of 250 pg/mL, the AUC was 0.903 (sensitivity=83.9, specificity=83.7). For identification of advanced DD and a cutpoint of 236 pg/mL, the AUC was 0.900 (sensitivity=83.9, specificity=84.1). For patients less than 65 years old with LVEF less than 45, cutpoint of 82 pg/mL was used, which gave an AUC of 0.916 (sensitivity=84.1, specificity=84.2). A cut-off of 70 pg/mL was used to identify advanced DD with an AUC of 0.912 (sensitivity=83.3, specificity=83.3).

Sex

Two studies investigated the relationship between sex and BNP.^156,158 Fuat et al.¹⁵⁶ compared the AUC of males and females and did not find a significant difference (males 0.79, females 0.80). Park et al.¹⁵⁸ compared the ability of BNP to identify male and female patients with LVEF less than 45 and advanced DD. The results of Park et al. are presented in Table 13.

Table 13

Effect of sex on AUC for BNP (Park et al., 2010).

Body Mass Index

Two studies examined the relationship between BNP and BMI.^158,159 Christenson et al.¹⁵⁹ grouped patients as normal (BMI <25 kg/m²), overweight (BMI 25 to 30 kg/m²), or obese (BMI >30 kg/m²), and demonstrated an inverse correlation of BNP with BMI. The AUC for diagnosis of decompensated HF in the three groups (<25kg/m², 25-30kg/m², and >30 kg/m²) were 0.78 (95% CI, 0.71 to 0.084), 0.62 (95% CI, 0.54 to 0.70), and 0.72 (95% CI, 0.66 to 0.79), respectively. Using a cutpoint of 100 pg/mL, sensitivity and specificity of BNP were 89 percent and 38 percent for normal weight patients, 85 percent and 38 percent for overweight patients, and 81 percent and 49 percent for obese patients, respectively.

Park et al.¹⁵⁸ also investigated the relation of BNP with BMI for the identification of patients with LVEF less than 45 and advanced DD. A similar inverse correlation trend was seen, more so with the advanced DD patients. Results are presented in Table 14.

Table 14

Effect of body mass index on diagnostic performance of BNP.

Renal Function

Park et al.¹⁵⁸ studied the effect of renal function on the ability of BNP to identify patients with LVEF less than 45 and advanced DD. Renal function was estimated by creatinine clearance calculated by the Cockroft-Gault equation. Patients were grouped as clearance less than 60 mL/min or greater than 60 mL/min. As can be seen, as renal function decreases the cutpoint must increase to maintain a similar sensitivity and specificity. The effect of decreased LVEF or advanced DD was overwhelmed by the effect of renal function, and had little effect on the optimal cutpoint. Results are presented in Table 15.

Table 15

Effect of renal function on diagnostic performance of BNP.

Study Design

Two studies used a prospective cohort design.^169,171 Study design could not be determined in one of the articles.¹⁷⁴ The remaining studies (n=17) used a cross-sectional design. The selected articles were published between 2003 and 2011 and were conducted in a wide range of regions: one in North America,¹⁵⁹ 18 in Europe,^{154,156,157,161-175} and one in Asia.¹⁵⁸

Population Characteristics

Most studies, with the exception of five,^{154,158,162,163,165} provided diagnostic information on the overall study sample presenting with dyspnea in a primary care setting. Some studies provided diagnostic information on populations grouped according to age^158,165,170 and sex.^{156,158,162,166,170} Some studies presented diagnostic information according to BMI status,^158,159 diabetes status,¹⁶¹ previous history of HF,¹⁶¹ LVEF,¹⁶³ renal failure,¹⁵⁸ and hemoglobin (Hb) measures.¹⁵⁸ One study presented groups according to their suspected HF/valvular disease (LVSD),¹⁶⁷ and one study grouped subjects according to diagnosis of major structural heart disease in patients with AF) compared with those with sinus rhythm (SR).¹⁶⁵

In all studies, study patients presented to a primary care facility with shortness of breath and were over 18 years of age. Seven studies had a patient population with mean or median ages from 60 to 69 years old.^{158,159,161-163,168,172} Eleven had populations with mean or median ages between 70 and 79 years.^{154,156,157,164-166,170,171,173-175} Two examined populations 80 years of age and over.^167,169

The percentage of males enrolled in each study ranged from 32.1 percent¹⁷⁰ to 100 percent¹⁵⁸ (mean=42.8%; median=46%). Sample size populations ranged from 14¹⁶³ to 1,321¹⁶⁵ (mean=239; median=140). The prevalence of HF in the study populations ranged from 4 percent¹⁶⁸ to 75 percent¹⁷³ (mean=31.2%; median=33.1%).

Component Studies

Most of the papers (n=17) were independent studies, publishing results on unique data sets. One study used data from the Echocardiographic Heart of England screening study (ECHOES),¹⁶¹ one reported results from the Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Diastolic Heart Failure (DIAST-CHF),¹⁷⁴ and one used results from the UHFO-IA.¹⁵⁴

Assays

All studies (n=20) used the ELECSYS^® proBNP Immunoassay to measure NT-proBNP.

Diagnosis of Heart Failure

The majority of studies (n=11) based the diagnostic reference standard solely on clinical judgment. Less than half of these had a reference standard agreed upon by at least two physicians^154,158 (mostly cardiologists), with eight studies basing the final diagnosis on the opinion of a single physician.^{157,159,167,168,170-173} The adjudication physicians each arrived at a diagnosis of HF based on their interpretation of all available clinical data; this often included echocardiography results. One of the studies used the Framingham criteria to aid in clinical judgment.¹⁷⁴

Of the remaining studies, four based the final diagnosis of HF both on clinical judgment and results of echocardiography,^{156,161,162,164,166} one based it on echocardiography results alone,^163,165 and one simply reported that the definitive diagnosis was “based on the Framingham criteria.”¹⁶⁹ One study used an outcome panel that evaluated all available information, excluding the NT-proBNP results.¹⁷⁵

Diagnostic Properties

The 20 studies evaluating NT-proBNP in primary care settings used several cutpoints ranging from 25¹⁷¹ to 6180¹⁶⁷ (mean=635; median=379) pg/mL or ng/L. Three studies^161,162,164 measured NT-proBNP in pmol/L. Reported sensitivities ranged from 44 percent¹⁶⁷ to 100 percent^164-166,169 (mean=80.6%; median=84.4 %), specificities from 3 percent¹⁶⁵ to 97 percent,^163,168 (mean=58.5% ; median=60.6%), and AUC of 0.70¹⁶¹ to 0.98¹⁶⁶ (mean=0.86; median=0.88). The majority of the studies focused on NT-proBNP alone (n=14), and the remainder focused on both BNP and NT-proBNP.^154,156-159 Appendix I Table I-4 presents data to answer KQ2.

When the appropriate data was available for extraction or calculation, 2×2 tables were prepared and forest plots of sensitivities, specificities, positive and negative LRs, DOR, and summary ROC curves are presented (Appendix I Figures I-13 to I-18).Three cutpoints were selected: lowest presented, the optimal cutpoint as chosen by the authors to examine in greater detail, and the manufacturers' recommended cutpoint of 125 pg/mL for patients younger than 75 years of age and 450 pg/mL for those patients 75 years of age or older. At least four studies were needed in each group to present summary estimates; however, for NT-proBNP according to manufacturers' cutpoint, only two studies satisfied our criteria and, thus, will not be presented.

When the optimal cutpoint chosen by the authors was used, the pooled sensitivity was 0.88 (95% CI, 0.81 to 0.93) and seven of the studies^{156,164,166-168,170,172} produced sensitivities greater than 0.90. A single study by Stahrenberg et al.¹⁷⁴ had a significantly lower sensitivity of 0.55 (95% CI, 0.44 to 0.65) due to a relatively high cutpoint of 22 pg/mL; however, they did produce a relatively good specificity 0.61 (95% CI, 0.47 to 0.74). The pooled specificity (0.58) was, as expected, not as high as the pooled sensitivity, as the authors tend to optimize sensitivity.

Using the lowest cutpoint chosen by the authors produced increased pooled sensitivity (0.90) when compared to the optimal cutpoint (0.88), with no decrease in pooled specificity (0.50). All but three studies^159,171,174 produced sensitivities greater than 0.90.

As with the summary plots, the ROC curves were developed based on the optimum and lowest cutpoints. The AUC were 0.86 (95% CI, 0.82 to 0.88) for the optimum cutpoint, and 0.82 (95% CI, 0.79 to 0.85) for the lowest cutpoint (Appendix I Figures I-19 to I-20).

Age

Two studies investigated the influence of age on the diagnostic ability of NT-proBNP.^158,165 In both cases the optimal cutpoint for identification of major structural heart disease (defined as LVEF <40, left ventricular DD, or right ventricular dilation) was higher in older patients. Shelton et al.¹⁶⁵ compared patients above and below the age of 75 years. They also compared the difference between patients in SR and those in AF. Park et al.¹⁵⁸ compared the performance of BNP for patients above and below 65 years of age for the identification of LVEF or advanced DD. Table 16 provides a summary of this data.

Table 16

Effect of age on diagnostic performance of NT-proBNP.

Sex

Five studies investigated the relationship between sex and the ability of NT-proBNP to diagnose HF.^{156,158,162,166,170} Using a regression model, Mikkelsen et al.¹⁶⁶ identified sex as a significant influence on NT-proBNP. The AUC for the diagnosis of HF in females was 0.97 (95% CI, 0.95 to 1.00) and 0.91 (95% CI, 0.83 to 0.98) for males. Due to the sex differences, the optimal cutpoints were different between males and females: 85 pg/mL and 110 pg/mL, respectively.

Nielsen et al.¹⁶² examined the ability of NT-proBNP to identify HF in men and women 50 years of age and above, as the prevalence of HF in those less than 50 years of age was very low. ROC curves for men gave an AUC of 0.93 (95% CI, 0.89 to 0.97) for men and an AUC of 0.90 (95% CI, 0.84 to 0.97) for women. Using a NPV of 97 percent, they suggest a cutpoint of 11 pmol/L for men and 17 pmol/L for women.

Fuat et al.¹⁵⁶ compared the ability of NT-proBNP to rule out the presence of HF in men and women. They maximized sensitivity without producing an unacceptable loss of specificity. The AUC for men was 0.79, and using a cutpoint of 100 pg/mL produced a NPV of 0.89 (95% CI, 0.74 to 1.00). Women had a slightly higher AUC of 0.82, and using a cutpoint of 150 pg/mL produced a NPV of 0.94 (95% CI, 0.88 to 1.00).

Linear regression analysis performed by Olofsson and Bowman¹⁷⁰ showed no significant difference in diagnosis of HF between males and females, while multiple linear regression showed that age and male sex was significantly associated with higher levels of NT-proBNP.

Park et al.¹⁵⁸ compared the ability of NT-proBNP to identify male and female patients with LVEF less than 45 and advanced DD. Data for multiple cutpoints and results of papers that used sensitivity and specificity as an outcome are shown in Table 17. Fuat et al.¹⁵⁶ maximized sensitivity, then specificity, and reported an outcome of NPV. This study is therefore not presented in Table 17.

Table 17

Effect of sex on diagnostic performance of NT-proBNP.

Body Mass Index

Two studies examined the relationship between NT-proBNP and BMI.^158,159 In a relatively large study of 685 patients, Christenson et al.¹⁵⁹ grouped patients as normal (BMI <25 kg/m²), overweight (BMI 25 to 30 kg/m²), or obese (BMI >30 kg/m²), and demonstrated an inverse correlation of NT-proBNP with BMI. The AUCs for a diagnosis of decompensated HF in the three groups (normal, overweight, and obese) were 0.77 (95% CI, 0.70 to 0.084), 0.64 (95% CI, 0.56 to 0.72), and 0.71 (95% CI, 0.65 to 0.77), respectively. Using the International Collaborative of NT-proBNP study cutpoints² of 450 pg/mL for under 50 years of age, 900 pg/mL for ages 50 to 75, and 1,800 pg/mL for ages over 75, sensitivity and specificity of BNP were 88 percent and 50 percent for normal weight patients, 68 percent and 51 percent for overweight patients, and 69 percent and 64 percent for obese patients, respectively.

Park et al.¹⁵⁸ also investigated the relation of NT-proBNP with BMI for the identification of patients with LVEF less than 45 and advanced DD. Results are presented in Table 18.

Table 18

Effect of body mass index on diagnostic performance of NT-proBNP.

Renal Function

Park et al.¹⁵⁸ also studied the effect of renal function on the ability of NT-proBNP to identify patients with LVEF less than 45 and advanced DD. Renal function was estimated by creatinine clearance calculated by the Cockroft-Gault equation. Patients were grouped as clearance less than 60 mL/min or clearance of 60 mL/min or over. Using multivariate regression analysis, clearance less than 60 ml/min was shown to be an independent determinant of NT-proBNP. The AUC, sensitivity, and specificity results are presented in Table 19.

Table 19

Effect of renal function on diagnostic performance of NT-proBNP.

BNP

For studies of diagnostic tests (KQ2), we used the QUADAS-2 to assess quality in four key domains: patient selection, index test(s), reference standard, and flow and timing. The questions in each domain are rated in terms of risk of bias (low, high, unclear) and concerns regarding applicability (low, high, unclear), with associated signaling questions to help with bias and applicability judgments (Figures 7 and 8, and Appendix I Table I-5).

Figure 7

Proportion (%) of all diagnostic studies using BNP with low, high, or unclear concerns regarding risk of bias in primary care.

Figure 8

Proportion (%) of diagnostic studies using BNP with low, high, or unclear concerns regarding applicability in primary care.

The potential for bias in the domain of patient selection was assessed on the basis of the enrollment of the study sample (consecutive, random, or convenience), the avoidance of a case-control design, and the avoidance of inappropriate patient exclusions. For this domain, 42 percent of studies (n=5) were rated as low risk for bias and 58 percent (n=7) were rated as unclear as to risk of bias. Studies were assessed as to patient population applicability to those targeted by the review question in terms of severity of the target condition, demographic features, presence of differential diagnosis or comorbid conditions, and setting of the study. Overall, 83 percent (n=10) of studies were assessed as high, 8 percent (n=1) as low, and 8 percent (n=1) as unclear for concern regarding applicability on this domain.

The potential for bias in the domain of the index test was assessed according to whether results were interpreted without knowledge of the results of the reference standard and whether a prespecified threshold was used for BNP cutpoints. Twenty-five percent (n=3) of studies were rated as low risk on this domain, 33 percent (n=4) were rated as high, and 42 percent (n=5) were rated as unclear. Studies were assessed on concerns of applicability on the basis of whether the index test methods varied from those specified in the review questions. Concerns about applicability on this domain were assessed as low for 67 percent (n=8) of studies, as high for 25 percent (n=3), and as unclear for 8 percent (n=1).

The potential for bias in the domain of the reference standard (i.e., the criteria used to confirm a diagnosis of HF) was judged on the basis of whether the reference standard was likely to correctly classify the target condition and whether the results were interpreted with knowledge of the BNP results. Studies were rated as low risk for 67 percent (n=8) of articles, high for 25 percent (n=3), and as unclear by 8 percent (n=1). Concerns about applicability were assessed as to whether the target condition, as defined by the reference standard, differed from the target condition specified in the review question. Sixty seven percent (n=8) of studies were assessed as low, 25 percent (n=3) were assessed as high, and 8 percent (n=1) were unclear on this domain.

The potential for bias in the domain of flow and timing was assessed on the basis of inappropriate intervals between index test and reference standard, standardized administration of reference standard among patients, and equal inclusion of patients in the analysis. Eighty three percent (n=11) of studies were assessed as low risk and eight percent (n=1) were unclear as to bias for this domain.

NT-proBNP

For studies of diagnostic tests (KQ2), the QUADAS-2 used to assess quality in four key domains: patient selection, index test(s), reference standard, was and flow and timing. The questions in each domain are rated in terms of risk of bias (low, high, unclear) and concerns regarding applicability (low, high, unclear), with associated signaling questions to help with bias and applicability judgments (see Figures 9 and 10, and Appendix I Table I-6).

Figure 9

Proportion (%) of diagnostic studies using NT-ProBNP with low, high, or unclear concerns regarding risk of bias in primary care.

Figure 10

Proportion (%) of diagnostic studies using NT-ProBNP with low, high, or unclear concerns regarding applicability in primary care.

The potential for bias in the domain of patient selection was assessed on the basis of the enrollment of the study sample (consecutive, random, or convenience), the avoidance of a case-control design, and the avoidance of inappropriate patient exclusions. For this domain, 40 percent of studies (n=8) were rated as low risk for bias and 5 percent (n=1) were rated as high risk. The remaining studies (n=11; 55%) were rated as unclear as to risk of bias. Studies were assessed as to patient population, applicability to those targeted by the review question in terms of severity of the target condition, demographic features, presence of differential diagnosis or comorbid conditions, and setting of the study. Overall, 65 percent (n=13) of studies were assessed as high for concerns about applicability on this domain, 20 percent (n=4) were rated as low, and the remainder (n=3; 15%) were rated as unclear on concern regarding applicability on this domain.

The potential for bias in the domain of the index test was assessed according to whether results were interpreted without knowledge of the results of the reference standard and whether a prespecified threshold was used for NT-proBNP cutpoints. Forty-five percent (n=9) of studies were rated as low risk and 35 percent were rated as high risk (n=7) and 20 percent (n=4) were deemed unclear on this domain. Studies were assessed on concerns of applicability on the basis of whether the index test methods varied from those specified in the review questions. Concerns about applicability on this domain were assessed as low for 70 percent (n=14) of studies and as high for 30 percent (n=6).

The potential for bias in the domain of the reference standard (i.e., the criteria used to confirm a diagnosis of HF) was judged on the basis of whether the reference standard was likely to correctly classify the target condition and whether the results were interpreted with knowledge of the NT-proBNP results. Seventy percent of studies (n=14) were rated as low risk, 10 percent (n=2) were rated as high, and 20 percent (n=4) were rated as unclear on this domain. Concerns about applicability were assessed as to whether the target condition, as defined by the reference standard, differed from the target condition specified in the review question. Sixty-five percent (n=13) of studies were assessed as low and 35 percent (n=7) were assessed as high on this domain.

The potential for bias in the domain of flow and timing was assessed on the basis of inappropriate intervals between index test and reference standard, standardized administration of reference standard among patients, and equal inclusion of patients in the analysis. Ninety percent (n=18) of studies were assessed as low risk of bias and 10 percent (n=2) were assessed as unclear on the domain of flow and timing.

BNP/NT-proBNP

Two primary outcomes were chosen to be assessed: sensitivity and specificity. For all studies that presented sensitivity and specificity data (BNP n=11;^{148-154,156-159} NT-proBNP n=17^{156-159,161-170,172-174}), the SOE was examined using a variety of cutpoints. For BNP the lowest cutpoint provided, the manufacturers' suggested, and the optimal cutpoint identified by the author were used. For NT-proBNP we used the lowest and optimal cutpoints.

The SOE for both BNP (Appendix I Tables I-7a to I-7c) and NT-proBNP (Appendix I Table I-8a to I-8c) were determined to be high for sensitivity and moderate for specificity at all cutpoints examined.

Precision

For both BNP and NT-proBNP, the CIs around the summary estimates for sensitivity and specificity for BNP and NT-proBNP are not precise. This domain was rated as imprecise (Table 20).

Table 20

Statistical summary of test performance characteristics based on the manufacturer, optimum, and lowest cutpoints in the primary care settings.

Characteristics of Studies in Decompensated Heart Failure Patients Using BNP Levels

Risk of Bias

The risk of bias was assessed based on the Hayden criteria⁵⁸ as described in the methods section (Appendix E) and results across studies are seen in Figure 11 (see also Appendix J Table J-1 for individual study ratings).

Figure 11

Assessment of risk of bias using the Hayden criteria for prognostic studies in decompensated HF population assessing BNP as the predictor. (a) source population clearly defined, (b) study population described c) study population represents source population, (more...)

For the studies including patients with decompensated HF and evaluating the predictive strength of BNP levels, there is low risk of bias for population description and selection, attrition, description of statistical analysis, and for how prognostic factors were addressed, with the exception that most studies did not provide reasons for indeterminate test results or missing data (item 3e).

Although, the outcome measurement was adequately defined in most studies, the majority of publications did not adequately measure the outcome (item 4b), and many studies reported data for composite outcomes only (item 4c). The risk of bias is high for the BNP studies in decompensated patients with respect to adequate measurement of outcomes and avoiding composite outcomes.

Confounding was particularly poorly addressed in this group of studies. Based on the a priori criteria, studies were assessed for selection of important confounders such as age, sex, BMI, and renal function as important covariates within the prognostic model. Within these 44 publications, only 43 percent of studies met criteria for measuring confounders or accounting for them in the design or analysis (items 5a, 5b). The risk of bias is high for confounding and most studies omitted at least one of the key confounders (BMI in particular).

Most of the study designs were observational cohorts (prospective) and the majority of studies established research questions specifically to assess BNP levels. However, some studies evaluated other cardiac markers and the focus of the research and the development of the prognostic models included evaluation of the BNP but was not primarily focused on BNP.

In summary, the overall risk of bias in studies evaluating BNP levels as a predictor of outcome in decompensated patients for HF, was rated as moderate because of concerns with adequacy of outcome measurement, use of composite outcomes only, and problems with identification and adjustment for key confounders.

Results

All tables showing the prognostic studies can be found in Appendix J.

BNP Levels Predicting Risk for All-Cause Mortality

Appendix J and Table 21 describe study outcomes and followup.

Table 21

Outcomes by length of time interval in decompensated population assessing BNP.

Admission, Discharge, and Change in BNP Levels and Prognosis Up to 31 Days

Five studies^{183,194,196,215,217} assessed admission BNP levels and attempted to evaluate all-cause mortality up to 30 or 31 days (Appendix J Table J-2). Two studies recruited subjects from emergency settings. One study²¹⁷ reported that admission BNP levels were independent predictors of 14 day mortality. The REDHOT II study¹⁹⁴ recruited subjects with BNP levels greater than 100 pg/mL; patients were randomized to having serial BNP measurements (admission, 3, 6, 9, and 12 hours post admission) that were communicated to the physician; the control group did not have serial measurement and assessment of BNP was at the discretion of the physician. The findings from the REDHOT II study suggest that knowledge of serial BNP measurements has a protective effect with respect to predicting 30 day mortality but this was not statistically significant. This study could also be classified as one assessing the impact of the use of BNP to guide treatment.

Three studies enrolling subjects admitted to hospital^183,196,215 attempted to evaluate the association between baseline BNP and subsequent 30 day mortality. Two studies evaluated serial measurements of BNP, including admission, 24 hours,^196,215 48 hours,²¹⁵ and at days three and five.¹⁹⁶ Neither study reported the predictive strength of admission BNP levels and subsequent mortality. Both these studies would suggest that serial measurements at 24 and 48 hours are significant predictors of 30 day mortality. One study¹⁹⁶ showed that change from baseline (reduction in BNP levels) was protective with respect to 30 day mortality. A single study¹⁸³ that was at high risk of bias evaluated patients admitted to an acute care center with BNP levels >100 pg/mL but reported no results from the logistic regression specific to BNP.

Admission, Discharge, and Change in BNP Levels and Prognosis From 2 to 3 Months

Four studies^{3,176,214,217} attempted to evaluate the predictive strength of BNP levels and all-cause mortality at 3 months (Appendix J Table J-3). All but one study recruited subjects from the emergency setting.²¹⁴ Two publications^3,217 evaluated the subjects from the BACH study but differed in the number of subjects with final adjudication of acute HF; both BACH publications showed admission BNP levels to be independent predictors of 90 day mortality. One of these publications³ showed admission BNP to be an independent predictor when considered as both a categorical, continuous, and log transformed variable in a simple statistical model (age, sex, BMI, creatinine) but not in a more complex model. The REDHOT trial,¹⁷⁶ showed that knowledge of serial BNP levels (admission, 3, 6,9, and 12 hour) was an independent predictor of 90 day all-cause mortality. A single study²¹⁴ recruited subjects admitted to hospital, evaluated a 10 percent change (decrease) relative to admission BNP levels and showed that this change in BNP levels was not a statistically significant predictor of 90 day mortality.

Admission, Discharge, and Change in BNP Levels and Prognosis at 6 to 11 Months

Five publications^{196,198,200,205,210} evaluated BNP levels and prediction of all-cause mortality from 6 to 11 months (Appendix J Table J-4). Two publications^198,205 had overlapping samples recruited from the same hospital center. One of these publications²⁰⁵ used log transformed BNP and showed it to be an independent predictor. The companion article¹⁹⁸ used admission BNP levels and showed a dose response effect; with increasing thresholds (quintiles) of BNP levels, the HR increased (from HR=2.75 (95% CI, 1.17 to 6.46) to HR=5.82 (95% CI, 2.62 to 12.97)). There was some concern with outcome measurement and the adjustment of confounders in these companion papers, suggesting the potential for increased risk of bias in these two publications. Another study²¹⁰ recruiting subjects form emergency settings and evaluating admission BNP levels showed that higher levels of BNP increased the HR for 6 month mortality (HR=1.84 (95% CI, 1.25 to 2.71) to (HR=3.22 (95% CI, 2.27 to 4.55)).

The two remaining studies evaluated change in BNP levels¹⁹⁶ and discharge BNP levels²⁰⁰ as predictors of all-cause mortality. In one study,¹⁹⁶ a decrease of BNP levels greater than 30 percent relative to admission (or <800 pg/mL) showed a protective effect from mortality. In the second study,²²² combining subjects who had discharge BNP levels greater than or equal to 360 pg/mL and a decrease of less than 50 percent, or increase (Group 3 vs. 1) showed the highest HR (Appendix J Table J-4).

Admission, Discharge, and Change in BNP Levels and Prognosis at 12 to 23 Months

There were seven publications that evaluated admission BNP levels from the BASEL cohort,^106,188 a German study (overlapping samples),^182,204 the PRIDE study,^213,216 and an independent study¹⁹³ for predicting 12 month all-cause mortality. Two studies^211,215 evaluated change or discharge levels of BNP.

All but two studies^193,211 recruited patients from emergency settings. All but one study²¹⁵ recruited subjects from emergency settings and evaluated admission BNP levels as predictors. One additional¹⁹³ study evaluated admission BNP levels but recruited subjects admitted to hospital but with a mixed population with 29.7 percent of subjects recruited from the community The seven publications^{106,182,188,204,213,215,216} that recruited patients from emergency settings, were generally at low risk of bias, with the exception of some concerns regarding verification or validity of the outcomes and potential confounding. One study with two publications,^182,204 undertook different model computations on the same dataset. (Appendix J Table J-5) shows the differences in the estimate of the HR varying from HR=2.45 (95% CI, 1.29 to 4.65) to HR=3.34 (95% CI, 1.61 to 6.97). Similarly, two studies from the PRIDE cohort²¹⁶ and the Boston site of the PRIDE cohort,²¹³ showed that admission BNP levels were independent predictors of all-cause mortality (HR=2.12 [95% CI, 1.37 to 3.27] and HR=2.53 [95% CI, 1.53 to 6.21]) at 12 months.

Two publications^106,223 based on subjects from the BASEL study, modeled admission BNP levels as a dichotomous and continuous variable, and both were independent predictors of 12 month mortality. The final study evaluating admission BNP levels also showed that BNP was an independent predictor of mortality at 12 months.¹⁹³

Two studies did not assess the prognostic value of admission BNP levels assessed but serial measurements²¹⁵ and discharge BNP levels.^211,215 The first study²¹⁵ showed that 24 and 48 hour and discharge BNP levels were all significant independent predictors of 12 month mortality. The second study²¹¹ had a primary aim to evaluate the prognostic merit of Type D personality type (distressed) as a predictor of mortality but did not find this factor (or symptoms of depression) to be significant; rather, discharge BNP was shown to be an independent predictor at 18 months.

Admission, Discharge, and Change in BNP Levels and Prognosis at 24 Months and Greater

There were three studies,^179,192,208 that evaluated prognosis at 24 months (Appendix J Table J-6). The single study²⁰⁸ evaluating admission BNP levels as a predictor of 24 month all-cause mortality had a primary objective to compare the value of human growth factor as a predictor; BNP was the reference biomarker, and was shown to be a significant predictor. A second study¹⁹² compared admission and discharge BNP levels and both were shown to be independent predictors at 24 months. The final study¹⁷⁹ evaluating prediction of 24 month all-cause mortality evaluated discharge BNP levels and this was not statistically significant.

Characteristics of Studies in Decompensated Heart Failure Patients Using NT-proBNP Levels

Risk of Bias

The risk of bias was assessed based on the Hayden Criteria⁵⁸ as described in the methods section of this report. Figure 12 shows the proportion of studies meeting the criteria assessed for risk of bias (see Appendix J Table J-12 for individual study ratings).

Figure 12

Risk of bias for prognostic studies using the Hayden criteria for both decompensated heart failure patients assessing NT-proBNP. (a) source population clearly defined, (b) study population described (c) study population represents source population, (more...)

For the studies including patients with decompensated HF and evaluating the predictive strength of NT-proBNP levels, there is low risk of bias for population description and selection, attrition, description of statistical analysis, and for how prognostic factors were addressed, with the exception that most studies did not provide reasons for indeterminate test results or missing data (item 3e).

Although, the outcome measurement was adequately defined in most studies, the majority of studies (66%) did not adequately measure the outcome (item 4b), and at least one third of the studies reported data for composite outcomes only (item 4c). The risk of bias is high for this group of studies with respect to adequate measurement of outcomes and avoiding composite outcomes.

Confounding was particularly poorly addressed in the studies evaluating NT-proBNP in decompensated HF patients. The a priori criteria for confounding assessed studies with respect to a minimum set of confounders that included age, sex, BMI, and renal function as important covariates. Only 41 percent of studies in this group met the criteria for measuring confounders (item 5a) and 32 percent accounted for them in the design or analysis (item 5b). The risk of bias is high for confounding (BMI in particular) in these studies.

Most of the study designs were observational cohorts (prospective) and the majority of studies established research questions specifically to assess BNP levels. However, some studies evaluated other cardiac markers and the focus of the research (and covariates in the prognostic models) was not primarily focused on BNP.

In summary, the overall risk of bias in studies evaluating BNP levels as a predictor of outcome in decompensated patients rated overall as moderate.

Study Outcomes and Followup Periods

Table 22 shows study outcomes and followup period for patients admitted to hospital for decompensated HF. Twenty-three^{1-3,213-217,224,225,228,234,238-240,242,243,245,247,248,250,251,256} of the 41 publications assessed all-cause mortality as a primary outcome using followup periods ranging from 2 months^1,225,228 to 81 months.²⁵⁶ The majority of these studies, with the exception of three,^214,217,247 used NT-proBNP collected at admission as a prognostic indicator for all-cause mortality. Four papers^{224,234,242,243} used discharge NT-proBNP and change in NT-proBNP from admission to discharge, along with admission NT-proBNP, as covariates in their models. One article²⁴⁷ used NT-proBNP measurements taken serially in combination with discharge, while another²¹⁵ added admission NT-proBNP to serial and discharge measures. One article²¹⁷ just used serial measurements of NT-proBNP. Five articles^{229,230,236,246,249} assessed cardiovascular mortality as an outcome, with followup periods ranging from one month²⁴⁹ to 15 months.²⁴⁶ All, but one,²⁴⁹ used admission NT-proBNP to predict cardiovascular mortality. Two articles^230,249 used serial measurements, along with change in NT-proBNP, in their models.

Table 22

Outcomes by length of time interval in decompensated population assessing NT-proBNP.

All-cause morbidity was assessed in three articles,^234,243,253 and cardiovascular morbidity outcomes were assessed in one.²²⁹ The remaining outcome measures consisted of composite outcomes combining various combinations including: cardiovascular mortality and cardiovascular morbidity,^{231,237,252,255,257} all-cause mortality and cardiovascular morbidity,^{1,226,227,241,254,258} all-cause mortality and all-cause morbidity,^{232-234,250,253,259} and cardiovascular mortality and all-cause morbidity.²⁴⁴ Of the articles assessing morbidity or composite outcomes, 10 used admission NT-proBNP alone as a prognostic indicator.^{1,234,235,237,241,250,252,254,255,260} The remaining publications used various combinations of admission, discharge, and change scores of NT-proBNP to predict morbidity and composite outcomes.

Results

NT-proBNP Levels Predicting Cardiovascular Mortality

A single study²⁴⁹ evaluated NT-proBNP levels at admission, at 12 hours post admission and the change from admission to 12 hour post admission to predict 30 day cardiovascular mortality (Appendix J Table J-18). These results were also stratified by subgroups of HF patients (chronic ischemic cardiomyopathy (ICM), decompensated non-ischemic cardiomyopathy (NONICM) and acute ischemia (AMI)). The findings in this study suggest that NT-proBNP levels after admission (at 12 hours or increase from baseline at 12 hours) are predictive of mortality but admission levels are not. There was some variation in statistical significance within the HF subgroups; the sample sizes were small relative to the covariates included in the model for the AMI and NONICM groups.

Two papers evaluated admission NT-proBNP levels at 6 months²³⁶ and 8.5 months²²⁹ as predictors of cardiovascular mortality (Appendix J Table J-19). Both studies showed that NT-proBNP was not a significant predictor, but both studies did not include important covariates in their prognostic models.

A single study evaluated NT-proBNP levels and cardiovascular mortality at 12²³⁰ and 15.5 months (Appendix J Table J-19). One study used the reduction of NT-proBNP levels greater than 30 percent relative to admission levels, as predictive of cardiovascular mortality; this study was rated as having some deficiencies with respect to identification and control of confounders. A second study compared admission NT-proBNP and log transformed NT-proBNP as predictors of cardiovascular mortality; although both HR estimates were significant, the log transformed value doubled the magnitude of the risk

Admission and Discharge NT-proBNP Levels Predicting Composite Outcomes

Design Characteristics of Studies

The prognostic value of BNP among patients with chronic stable HF was assessed in 15 publications.^222,261-274 All of the included studies measured BNP at admission to the study. As this group of studies examined stable HF, the measurement of BNP at discharge or change in BNP between admission and discharge are not relevant to the question. One article measured both BNP and NT-proBNP and is included in this section for a total of 16 papers.²⁷⁵ One article²²² used an RCT design and the remaining studies (n=15) used prospective cohort designs. The selected articles were published between 2003 and 2011 and were conducted world-wide including: four in North America,^261-263,267 and seven in Europe.^{264,265,268,270,273-275} Two publications were from studies conducted in multinational sites,^269,271 one from Turkey²⁶⁶ and two were unclear as to region of conduct.^222,261

Four articles reported patient population with mean or median ages ranging from 60 to 69 years.^{222,261,266,270} Three had a somewhat older patient populations with mean or median ages between 70 and 79 years.^272-274 Nine articles had populations with mean ages less than 60.^{262-265,267-269,271,275} Two papers reported age ranges of 15 to 84.^263,275 The percentage of males enrolled in each study ranged from 59 percent²⁶¹ to 89 percent²⁶⁴ (mean=68.2%, median=72.5%). Sample size populations ranged from 46²⁷² to 1,294²⁷⁴ (mean=398, median=254).

Table 23 shows study outcomes and durations for each publication grouped by the outcomes. Some papers reported study duration as endpoints of years or months and reported durations ranging from 6 months to 24 months. Most reported mean or median study durations ranging to a median of 68 or a mean of 55.8 months followup.

Table 23

Outcomes by length of time interval in stable population assessing BNP.

Risk of Bias

The risk of bias was assessed based on the Hayden criteria⁵⁸ as described in the methods section (Appendix E) and findings are shown in Figure 13 (also Appendix J Table J-25).

Figure 13

Risk of bias for prognostic studies using the Hayden criteria for stable population assessing BNP. (a) source population clearly defined, (b) study population described (c) study population represents source population, or population of interest (a) (more...)

The populations for this group of studies was mostly suitably defined, described, and represented the population of interest. Only one paper did not define the population adequately,²⁷¹ and one paper's²⁶⁸ population was considered not representative of the study's source population or population of interest. There is low risk of bias for population description and selection.

The description of attrition was not adequately described in a number of papers.^{222,268,270,272,274,275} Overall, the risk of bias is moderate for study attrition.

The prognostic factors were fairly well addressed. BNP was appropriately defined and measured in all but two papers.^268,274 The other prognostic factors were well defined and measured in all but one paper.²⁷⁵ The indeterminate results or missing data was less well addressed by a few papers.^{222,270,272-274} There is low risk of bias for the BNP and low risk of bias for the other prognostic factors.

Outcome measurement was defined by most studies, with the exception of one.²⁷¹ We set fairly stringent criteria for obtaining accurate data and only two studies met these criteria.^267,275 Composite outcomes are not recommended by Hayden and as we included composite outcomes a number of studies did not meet this criterion.^{264-268,272,273} The risk of bias for the outcomes is moderate.

Confounding was particularly poorly addressed. According to the criteria we expected studies to consider age, sex, BMI, and renal function as important covariants. Some studies met these criteria.^{262,263,267-269,272,275} The risk of bias from confounders (BMI in particular) is high (Figure 13)

Analysis was appropriately conducted in all the studies. Most of study the designs were observational cohorts and the question posed for the reports most often looked at the predictive value of BNP in the population described. There is low risk of bias for analysis.

In summary, the risk of bias in this group of papers for KQ3 is rated as moderate.

Results

Design Characteristics of Studies

The prognostic value of NT-proBNP among patients with chronic stable HF was assessed in 88 publications.^4,53,275-362 One additional article²⁷⁵ measured both BNP and NT-proBNP and is also included in this section, for a total of 89 papers.

Two articles were RCTs of NT-proBNP-guided therapies versus non NT-proBNP-guided therapies.^4,53 Four articles were secondary analyses of data initially collected in RCTs; however, the secondary analyses did not account for the groups to which participants were randomized.^{279,286,301,309} One was a nonrandomized controlled clinical trial,²⁹⁸ and one³¹⁷ was a post hoc analysis of an RCT. One study³⁴² used a cross-sectional design and two did not report the study design used.^322,346 Three papers^275,352,360 used a retrospective cohort design and the remaining 76 publications used prospective cohort designs. All articles were published between 2001 and 2012 and were conducted in the following parts of the world: five in North America,^{293,305,314,338,345} 11 in Asia,^{289,290,297,298,302,311,313,327,332,336,346} and one in Austria.⁴ Sixteen publications were from studies conducted in multinational sites,^{53,284,286,301,307,309,317,318,322,328,331,339,340,344,351,356} and four^{276,334,335,341} were unclear as to region of conduct. The remainder (n=52) were published in Europe.

Companion Articles

Several authors published results from large studies, including one²⁷⁹ from the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, one³³³ from the MUerte Sȗbita en Insuficiencia (MUSIC) study, three^301,309,351 from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA), two^53,345 from the Cardiovascular Health Study (CHS), and one³⁰⁵ from the Assessment of Doppler Econocardiography Study in Prognosis and Therapy. One article²⁷⁵ was unclear as to study affiliation and nine published results on companion data sets.^{280,281,286,288,297,298,313,326,327} The remaining articles (n=71) were independent studies, publishing results on unique data sets.

Risk of Bias

The risk of bias was assessed based on the Hayden criteria⁵⁸ as described in the Methods section, Appendix E, Figure 14, and Appendix J Table J-32 shows the percentage ratings for risk of bias for studies evaluating NT-proBNP in stable HF populations.

Figure 14

Risk of bias for prognostic studies using the Hayden criteria for stable population assessing NT-proBNP. (a) source population clearly defined, (b) study population described (c) study population represents source population, or population of interest (more...)

As seen in Figure 14 the populations for this group of studies were, for the most part, suitably defined (98 percent) and described (99 percent) with the exception of two papers.^310,353 It was clear in 96 percent of papers that the study population represented the source population or the population of interest, with one paper's³⁰⁴ population not representing the source population or the population of interest and three^295,337,353 being unclear as to whether this was the case. Therefore, all of the domains within this area of bias are rated as low risk of bias; the overall rating for this area of bias is also low.

Eighty-one percent of articles described their study's completeness of followup and 82 percent were assessed as having adequate completeness of followup. Attrition was not adequately described in two articles,^305,323 and we could not ascertain whether attrition was adequately described and complete in nine articles.^{275,298,300,327,328,342,345,351,360} In four other articles,^{288,289,344,349} completeness of followup was adequate, yet the description of followup was either unclear^289,349 or inadequate.^288,344 In two articles,^276,348 attrition was not adequately described and we could not ascertain whether followup was completed. A rating of unclear was assigned to each domain and an overall rating of unclear to the risk of bias for study attrition.

NT-proBNP and other prognostic factors were appropriately defined and measured in all except two included article.^282,290 The issue of indeterminate results or missing data for both NT-proBNP and other prognostic factors were less well addressed by a some papers,^{278,280,289,298-300,302,320,324,328,342,348,353,357,360,361} although the published reports do not suggest results were biased. The domain-specific and overall risk of bias rating for prognostic factor measurement is low.

Outcomes were defined in 98 percent of publications (low risk of bias), with the exception of two articles.^298,327 Fairly stringent criteria for obtaining accurate data on outcomes were set and only 30 of the 89 included articles (34 percent)^{53,275,280,281,283,286,288,296,303,312,320,321,323,329,338,339,341,347,350-360,362} measured the outcomes appropriately (high risk of bias). Twenty-one percent of studies (n=19) used composite outcomes only in their analysis and did not analyze any single outcome in multivariable analyses.^{53,285,287,294,303,305,306,311,317,321,322,324,333,336-338,340,348,353} The overall risk of bias for outcome measurement is high.

Confounding was particularly poorly addressed. According to the a priori criteria, studies were expected to measure age, sex, BMI, and renal function as important covariates. Fifty-six (63 percent) of the 89 articles met these criteria (low risk of bias). In publications that measured confounders, the means of adjustment was typically a multivariable regression analysis (low risk of bias). The overall risk of bias for measuring and accounting for confounding is high.

Analyses were appropriately conducted in all of the included articles. Most of the study designs were observational cohorts and the question posed for the reports most often looked at the predictive value of NT-proBNP in the population described. Consequently, a low risk of bias was assigned to this area.

For the seventh potential area of bias, it was considered whether the included articles were designed to test the prognostic value of NT-proBNP, rather than being secondary analyses of data collected for other purposes. All except five papers^{298,317,332,339,341} were adequately designed for prognostic study, earning a low risk of bias to this area.

Results

Chronic Stable Heart Failure and NT-proBNP Predicting All-Cause Mortality

Table 24 describes study outcomes and followup periods for studies assessing mortality outcomes (n=69). Sudden death was considered to be part of all-cause death. Pump failure death was not a primary study outcome. Since we included articles that performed multivariable analyses, measures of association reported in the text are adjusted in the analyses for the influence of covariates. Two articles within which the authors failed to report the length of followup were not considered.^301,309

Table 24

Outcomes by length of time interval in stable population assessing mortality for NT-proBNP.

Fifty-two articles included all-cause mortality as an outcome in the assessment of the predictive value of NT-proBNP in persons with chronic and stable HF (including the two publications that did not reports lengths of followup) (Appendix J Table J-33).^{4,275-282,284,286,288,290-292,295,296,299-302,307-309,311,313-315,317,320,321,326-332,336,342,344,345,348,350,353,355-360,362}

NT-proBNP Levels and Prognosis 6 Months or Less

Two papers^279,321 reported a followup of 6 months or less. In the first paper,²⁷⁹ an adjusted NT-proBNP value >1,767 pg/mL was a highly significant risk indicator in the model with RR=2.17 (95% CI, 1.33 to 3.54). In the second paper,³²¹ NT-proBNP level was a strong independent predictor of 6 month mortality, with a seven-fold risk of early death (OR=7.6, 95% CI, 1.4 to 40.8).

NT-proBNP Levels and Prognosis From Greater Than 6 Months to 12 Months

Five papers^{4,277,292,344,359} followed up participants for periods between 6 and 12 months, with two articles including persons with mean ages of 63³⁴⁴ and 65 years.³⁵⁹ Of the remaining three papers, two^277,292 included persons with a mean age of approximately 50 years and one⁴ contained subjects with a mean age of over 71 years. Two papers reported NT-proBNP cutpoints of >1,490²⁷⁷ and >1,548 pg/mL.²⁹² One paper³⁴⁴ reported an adjusted HR=1.43 per standard deviation (SD) unit increase, but did not reach statistical significance (95% CI, 0.89 to 2.3). Three articles reported chi-squares of 20.2 (p<0.001),³⁵⁹ 13.8 (p=0.0002),²⁹² and 6.03 (p=0.01),²⁷⁷ all of which suggest predictive values for NT-proBNP. One article⁴ did not report results of the multivariate analysis.

NT-proBNP Levels and Prognosis From Greater Than 12 Months to 24 Months

Eight articles^{276,278,286,290,291,320,326,332} reported followups of greater than 12 months and up to 24 months. One of these articles²⁷⁶ did not report any outcome data and will not be discussed further. Of the remaining papers, three^290,320,332 included persons with mean ages of 71 years, one²⁷⁸ used populations with mean ages of 82 and 50, and two^291,326 included persons with mean ages of 51 years. One paper²⁸⁶ did not report on the age of study participants. Reported measures of association in four articles^{286,320,326,332} were above 1.0 (indicating NT-proBNP is predictive of all-cause mortality) yet CIs included the null value in two cases,^326,332 the exception were HRs of 1.16 (95% CI, 1.042 to 1.291),³³² 2.58 (95% CI, 1.24 to 5.37),³²⁰ 4.02 (95% CI, 2.63 to 6.11),²⁸⁶ and 2.07 (95% CI, 1.76 to 2.46).²⁸⁶ The remaining three articles reported a chi-square of 13.6 (p<0.001),²⁹⁰ 14.2 (p<0.001),²⁹¹ and 26.95 (p=0.0001),²⁷⁸ all of which suggest predictive values for NT-proBNP.

NT-proBNP Levels and Prognosis From Greater Than 24 Months to 36 Months

Nineteen articles^{280-282,284,288,295,296,300,301,307,309,317,327-329,336,353,355,360} reported followups of greater than 24 months and up to 36 months. Sample sizes ranged from 50²⁹⁵ to 1,503.³¹⁷ Mean or median age ranges encompassed 60 to 69 years in 12 articles,^{282,284,288,295,296,300,317,327,328,336,355,360} and 70 to 79 years in five publications.^{280,281,307,329,353} One article did not report on population age. Authors reported cutpoints in 10 articles,^{278,281,295,296,317,327,329,336,353,355} ranging from >641 pg/mL³²⁷ to 10,000 pg/mL.²⁹⁵ Three papers adjusted HR based on decrements including one SD unit increase in NT-proBNP,^282,360 and a 500 pg/mL increase.²⁸⁴ Reported point-estimate HRs ranged from 1.03 per pg/mL increase²⁸⁴ to 4.2.²⁹⁶ All point estimates, except the ones calculated in two articles,^284,331 were statistically significant at the five percent level. In one paper³⁵⁵ NT-proBNP level was a strong independent predictor of all-cause mortality, with almost a three-fold risk of early death (OR=2.7; 95% CI, 1.3 to 5.7) Three papers^278,327,336 found NT-proBNP to have an independent predictive value, but the authors only reported chi-square test statistics rather than measures of association.

NT-proBNP Levels and Prognosis From Greater Than 36 Months to 48 Months

Nine articles^{302,308,313-315,331,342,357,362} reported followups of greater than 36 months and up to 48 months. Sample sizes ranged from 148³⁴² to 992.³⁶² Mean or median age ranges encompassed 50 to 59 years in one paper,³¹⁴ 60 to 69 years in six articles,^{313,315,331,342,357,362} and 70 to 79 years in two publications.^302,308 Three articles reported cutpoints of >796 pg/mL,³¹³ 1,000 pg/L,³⁶² and 1,720 pg/mL.³⁵⁷ Three of the nine papers adjusted HR based on decrements of NT-proBNP. Decrements included a one log unit (1 log pg/mL) increase,^308,331 a change of 2,000 pg/mL,³¹⁴ or a 100 pg/mL increase.³¹⁵ All adjusted HR indicated positive associations between higher values of NT-proBNP and all-cause mortality. Reported point-estimate ranged from HR=1.01 per 100 pg/mL increase³¹⁵ to HR=4.3.²⁸⁰ One article³¹³ reported a chi-square of 2.195 (p=0.0282). All point estimates, with the exception of one,³³¹ were statistically significant at the five percent level.

NT-proBNP Levels and Prognosis From Greater Than 48 Months to 60 Months

Five articles^{299,311,350,356,358} reported followups of greater than 48 months and up to 60 months. Sample sizes included 285,³¹¹ and 1,087,²⁹⁹ and 1,844.³⁵⁰ Two of the three articles included mean or median age groups ranging from 70 to 75.^299,311,356 One article³⁵⁰ did not report the age of their study population. Two articles reported statistically significant HRs, indicating positive associations between higher values of NT-proBNP and all-cause mortality. Reported point-estimate included: HR=1.006 (95% CI, 1.004 to 1.009),³¹¹ HR=2.06 (95% CI, 1.68 to 2.52),²⁹⁹ and HR=3.2 (95% CI, 2.69 to 3.79).²⁹⁹ In one article,³⁵⁶ baseline natural logarithm NT-proBNP as a continuous variable was independently associated with an increased risk of all end points, even after adjustment for several other baseline characteristics; however, use of angiotensin receptor blocker Irbesartan was associated with improved outcomes in patients with NT-proBNP below, but not above, the median levels. Adjusted HRs showed positive association between higher values of NT-proBNP and all-cause mortality.³⁵⁸ The final article³⁵⁰ did not report outcome data.

NT-proBNP Levels and Prognosis Greater Than 5 Years

Four studies (six reports) examined all-cause mortality for followup periods that were longer than 5 years.^{275,330,345,348,356,358} Mean or median age ranges encompassed 50 to 59 years in three papers,^275,330,348 and 70 to 79 years in the remaining three publications.^345,348,356 Authors reported cutpoints in three articles,^345,348,356 ranging from 190 pg/mL³⁴⁵ to 808 pg/mL,³⁴⁸ with one³⁴⁸ reporting various cutpoints based on sex and beta-blocker use. One paper²⁷⁵ reported results that were not statistically significant, although a statistically significant result was found after adding midregional pro-atrial natriuretic peptide (MR-proBNP) to a model with BNP and NT-proBNP already included. Prior to the addition of MR-proBNP, NT-proBNP was an independent predictor (p<0.05) of all-cause mortality. Another paper³³⁰ found NT-proBNP to have an independent predictive value, but the authors only reported chi-square test statistics rather than measures of association. Of the remaining three papers, two^345,348,358 had adjusted HRs indicating positive associations between higher values of NT-proBNP and all-cause mortality. Reported point-estimate ranged from HR=1.89 per 100 pg/mL increase to HR=3.37.³⁴⁸ All point estimates were statistically significant at the five percent level (Table 24).

NT-proBNP Levels Predicting All-Cause and Cardiovascular Morbidity

Table 25 describes study outcomes and followup period for articles assessing all-cause and cardiovascular morbidity outcomes (n=12).

Table 25

Outcomes by length of time interval in stable population assessing morbidity for NT-proBNP.

Twelve studies^{4,276,281,283,286,290,302,308,309,319,332,347} examined the prognostic value of NT-proBNP for all-cause and cardiovascular morbidity in persons with stable HF (Appendix J Table J-35 and Table J-36) Eight studies^{281,286,290,302,308,309,319,332} investigated morbidity as some form of hospitalization, including first cardiovascular hospitalization^308,309 or time to first hospitalization,³⁰² hospital admission for HF,^286,290,332 all-cause hospitalization,²⁸¹ or rehospitalization with worsening HF.³¹⁹ Three of these eight studies^290,302,309 also included a composite outcome of hospitalization and all-cause mortality.

Three studies defined morbidity as a decision to initiate cardiac transplant,²⁷⁶ change in NYHA class and quality-of-life,²⁸³ or worsening renal function.³⁴⁷ One study⁴ reported that NT-proBNP was the strongest prognostic indicator of first HF rehospitalization and a composite outcome of first HF rehospitalization and death; however, the authors did not show any regression results and this study will consequently not be considered further in this section.

Eleven studies included samples drawn from HF clinics. Mean ages of participants ranged from 56²⁷⁶ to 73;³⁰⁹ five studies^{290,302,308,309,332} included persons with mean ages between 71 and 73. One study²⁸³ stratified mean age data by participant subgroup, with the highest mean age being 70 years. Another study²⁸⁶ reported that 71 percent of the sample was aged less than 70 years, while 29 percent were aged 70 years or above. One study²⁸¹ stratified participants by NT-proBNP cutpoint and reported a mean age of 69 years (<1,381 pg/mL) or 75 years (>1381 pg/mL). A majority of participants were male in all studies, with the proportion of males ranging from 0.55²⁸³ to 0.84.³³²

Nine studies reported mean lengths of followup in the range of 12²⁸³ to 48 months.³⁰⁸ One study²⁷⁶ indicated followup lasted anywhere from 3 to 6 months, depending on the participant; one study reported a median length of followup of 28 months.²⁸¹ Sample sizes ranged from 78²⁸³ to 3,916.³⁰⁹ Mean sample size was 875, including the two largest studies (n=3,342,³⁰⁹ n=3,916²⁸⁶). Excluding the two largest studies, mean sample size was 264.

For most outcomes, higher levels of NT-proBNP were predictive of increased morbidity in persons with stable HF. Results in all except one study²⁸³ showed this positive association. In only one study³⁰² did the results fail to achieve statistical significance.

Hospitalization

Findings for morbidity measured as some form of hospitalization did not vary in terms of mean age, proportion of males, or length of followup. The largest effect was observed in a 48 month study of 354 persons,³⁰⁸ where baseline log NT-proBNP and log NT-proBNP measured after 6 months of followup, were both associated with increased unplanned cardiovascular hospitalizations. Adjusted HRs and 95% CIs (shown in brackets) were 3.16 (2.24 to 4.46) for baseline log NT-proBNP and 2.45 (1.50 to 4.01) for 6 month log NT-proBNP. The next largest effect was observed in a 23 month study (n=3,916) where the adjusted HR=2.66 (2.19 to 3.22) for persons above a cutpoint of 895 pg/mL. The authors found a cutpoint of 1,007 pg/mL to be optimal for prognostic purposes, with an AUC of 0.69, sensitivity of 70 percent, and specificity of 59 percent. In the other large study, consisting of 3,342 participants and an average followup of 32 months,³⁰⁹ the adjusted HR for a first cardiovascular hospitalization was HR=1.36 (1.29 to 1.44) for each 1-unit increase in log NT-proBNP.

In a study lasting 14 months,³³² the positive association between NT-proBNP and hospitalization was more muted, with an adjusted HR=1.07 (1.00 to 1.14; p=0.03).³³² Note, though, that a 44 month study of time to first hospitalization found an adjusted HR=1.01 (0.96 to 1.05).³⁰²

One 21 month study³¹⁹ of rehospitalization due to worsening HF dichotomized NT-proBNP at a cutpoint of 1,474 pg/mL. Persons with NT-proBNP values above 1,474 pg/mL had faster times to rehospitalization (HR=1.26; 95% CI, 1.03 to 1.55). Similar results were reported in a study with a median followup of 28 months, where NT-proBNP values above 1,381 pg/mL were associated with faster times to hospitalization (HR=1.71; 95% CI, 1.24 to 2.36).²⁸¹ This study also reported that a doubling of NT-proBNP levels would lead to faster hospitalization (HR for log₂ NT-proBNP: HR=1.19; 95% CI, 1.09 to 1.31). Another study²⁹⁰ involving 24 months of followup claimed higher NT-proBNP levels were positively associated with hospitalization for HF, but the authors only reported a chi-square test statistic (11.2) and p-value (p <0.01). This study²⁹⁰ also showed Kaplan-Meier curves depicting greater hospitalization for persons with NT-proBNP levels >1,556 pg/mL.

Three studies featured a composite outcome of hospitalization and mortality. One 24 month study²⁹⁰ only provided a Kaplan-Meier curve, which showed shorter times to either outcome in persons with NT-proBNP levels >1,556 pg/mL. A 32 month study³⁰⁹ found an adjusted HR=1.64 (95% CI, 1.54 to 1.74) and a 44 month study³⁰² found a non-significant adjusted HR=1.03 (95% CI, 1.00 to 1.06).

Besides the studies discussed above,^290,319 the only other hospitalization study that provided cutpoints was the 48 month investigation of first unplanned cardiovascular hospitalization.³⁰⁸ This study reported elevated risks of hospitalization at each of five levels of NT-proBNP, with the levels based on quintiles of baseline NT-proBNP (i.e., ≤474, 475 to 1,090, 1,091 to 2,529, 2,530 to 5,532, ≥5,533 (all values in pg/mL).

Other Morbidity Outcomes

Three studies^276,283,347 examined other morbidity outcomes besides hospitalization; all found strong predictive effects for NT-proBNP. The odds of being recommended for cardiac transplant were 10.6 times greater (95% CI, 3.7 to 14.5) in persons with an NT-proBNP value greater than 1,000 pg/mL in a study of 550 HF patients.²⁷⁶ In a study of 125 persons with HF, the risk of worsening renal function was 3.6 times greater (95% CI, 1.9 to 7.0) per standard deviation unit increase in log NT-proBNP.³⁴⁷ At a cutpoint of 696 pg/mL, NT-proBNP showed 92.9 percent sensitivity, 54.6 percent specificity, and an AUC of 0.80 (95% CI, 0.72 to 0.89) to predict worsening renal function.

A 12 month study examined two outcomes, namely improvements in NYHA class (n=78) or quality-of-life (n=71).²⁸³ The authors measured quality of life using the Minnesota Living with Heart Failure Questionnaire.³⁶³ Resistance to improvement in NYHA class was associated with low baseline NT-proBNP (OR=0.49; 95% CI, 0.31 to 0.78 on log NT-proBNP). Thus, high pre-treatment NT-proBNP levels suggested potential improvement in functional status. The authors did not report multivariable results for quality-of-life because model fit was poor.

NT-proBNP Levels Predicting All-Cause Mortality and All-Cause Morbidity

Table 26 describes study outcomes and followup period for articles assessing all-cause mortality and all-cause morbidity outcomes (n=3).

Table 26

Outcomes by length of time interval in stable population assessing all-cause mortality and all-cause morbidity for NT-proBNP.

Three studies^279,286,293 examined all-cause mortality and all-cause morbidity, which was defined as hospitalization^279,293 in two studies. The third study²⁸⁶ reported a composite outcome of “mortality and morbidity”, yet the authors did not clearly define morbidity. The studies included outpatients with HF. Proportions of males and mean ages were 0.81 and 63 years,²⁷⁹ 0.68 and 57 years,²⁹³ and 0.80 with mean age unreported.²⁸⁶ Sample sizes and lengths of followup were 1,011 participants and a mean of 5.3 months,²⁷⁹ 204 participants and a median of 36 months,²⁹³ and 3,916 participants and a mean of 23 months.²⁸⁶

In all cases, higher levels of NT-proBNP were associated with the composite outcomes. The adjusted relative risk was 2.11 (95% CI, 1.54 to 2.90) in the 5.3 month study for persons with an NT-proBNP level >1,767 pg/mL; adjusted HRs (CIs) were 1.23 (1.12 to 1.35) for persons with a level >1,000 pg/mL in the 36 month study²⁹³ and 2.20 (1.92 to 2.51) for participants with a level >895 pg/mL in the 23 month study.²⁸⁶ (Appendix J Table J-37)

NT-proBNP Levels Predicting Cardiovascular Mortality and Cardiovascular Morbidity

Table 27 describes study outcomes and followup period for articles assessing cardiovascular mortality and cardiovascular morbidity outcomes (n=8).

Table 27

Outcomes by length of time interval in stable population assessing cardiovascular mortality and cardiovascular morbidity for NT-proBNP.

Eight studies in 12 publications^{285,287,294,301,309,310,312,318,319,334,349,351} examined cardiovascular mortality and cardiovascular morbidity (Appendix J Table J-38). Three publications^301,309,351 used data from the CORONA study and another three publications^285,287,319 used data from a HF clinic in Germany. The main study publications for these two sets of papers were the ones with the most participants.^301,319 All eight studies included outpatients with HF. Proportions of males ranged from 0.65³¹⁸ to 1.00.²⁹⁴ Mean ages ranged from 54³¹⁰ to 73³⁰¹ years. The smallest sample size was 100³¹⁰ and the largest was 3,664.³⁰¹ The mean sample size was 601 including CORONA (n=3,664)³⁰¹ and 164 excluding CORONA. Mean lengths of followup were 6 months,³³⁴ 17 months,³¹⁸ 20 months,³¹⁹ 22 months,³¹² and greater than 24 months.^{294,301,310,349}

A 6 month study³³⁴ found NT-proBNP levels above 2061 pg/mL to be positively associated with a composite outcome of cardiac death, heart transplantation, or HF hospitalization (HR=2.56; 95% CI, 1.36 to 4.82). A 17 month study³¹⁸ examined three different cutpoints and found similar positive associations with a composite outcome of cardiovascular mortality, HF hospitalization, myocardial infarction, or stroke. Adjusted HRs (CIs) for each cutpoint were 3.1 (1.20 to 8.20) for >100 pg/mL, 5.8 (1.3 to 26.4) for >300 pg/mL, and 8.0 (2.6 to 24.8) for >600 pg/mL.

The longest of the three German HF clinic papers³¹⁹ reported a mean followup of 20 months. This article contained information on 341 persons recruited between March 2003 and November 2005. The composite outcome was cardiac death, need for a cardiac assist device, or urgent cardiac transplantation. Time to event was faster in persons with NT-proBNP levels greater than or equal to 1,474 pg/mL (HR=1.56; 95% CI, 1.23 to 1.98). An earlier publication²⁸⁵ from the same clinic reported on 162 persons recruited between March 2003 and November 2004. These persons were followed for a mean of 13 months. Time to a composite outcome of cardiac death or urgent cardiac transplantation was faster in persons with NT-proBNP levels above 1,129 pg/mL (HR=3.79; 95% CI, 1.62 to 8.89). The first publication²⁸⁷ from this research group reported on 73 participants followed for a mean of 5.6 months. The composite outcome was rehospitalization due to worsening HF, cardiac death, or urgent cardiac transplantation. The adjusted HR for a cutpoint of 2,283 pg/mL was HR=8.33 (95% CI, 2.65 to 26.20).

A study of 103 persons with mean followup of 22 months found NT-proBNP was not associated (p=0.2) with cardiovascular mortality or HF rehospitalization.³¹² The authors did not report HRs for NT-proBNP or any other variables that were non-significant in their multivariable regression model.

Besides the CORONA publications,^301,309,351 three other studies^294,310,349 followed participants for over 24 months. A 100-person study³¹⁰ with 25 months of mean followup reported an odds ratio of 1.27 (95% CI, 1.07 to 1.51) for a cutpoint of 1,000 pg/mL. The composite outcome was cardiovascular mortality and HF hospitalization. A 28 month study²⁹⁴ examined the occurrence of cardiovascular mortality or cardiovascular hospitalization in 163 men. When the multivariable regression model included dichotomized covariates for dehydroepiandrosterone sulphate levels and Beck Depression Inventory scores, men with NT-proBNP levels >500 pg/mL had a small increase in risk for the outcome (HR=1.02; 95% CI, 1.01 to 1.03). When these covariates were treated as continuous in the model, the increase in risk was statistically nonsignificant (HR=1.01; 95% CI, 1.00 to 1.03; p=0.09). A 37 month study³⁴⁹ of 107 persons showed an increased odds of cardiovascular mortality or HF hospitalization in participants with a log-transformed NT-proBNP level at or above a log-transformed cutpoint of 2.47 pg/mL (OR=4.16; 95% CI, 1.29 to 13.44).

Turning to the three CORONA articles,^301,309,351 participants were followed for a mean of 32 months. The primary composite outcome was cardiovascular mortality, nonfatal MI, or nonfatal stroke. A secondary composite outcome was any coronary event, which included sudden death, fatal or nonfatal MI, coronary revascularization, ventricular defibrillation by an implantable defibrillator, resuscitation from cardiac arrest, or hospitalization for unstable angina. The authors also had a post hoc outcome called atherothrombotic endpoint (i.e., fatal or nonfatal MI or fatal or nonfatal non-hemorrhagic stroke). The paper³⁰¹ with the largest sample size (n=3,664) reported the impact of log-transformed NT-proBNP on the aforementioned three composite outcomes. These same results were also reported in a slightly earlier paper³⁰⁹ where the CORONA team analyzed 3,342 persons who had complete data for all of the variables that were included in the regression analyses. Adjusted HRs (CIs) for each log unit change in NT-proBNP were 1.59 (1.48 to 1.71) for the primary outcome, 1.47 (1.36 to 1.59) for any coronary event, and 1.24 (1.10 to 1.40) for atherothrombotic outcomes.^301,309 The third CORONA paper in this series analyzed a subset of 1,449 persons for whom researchers had measured soluble ST2.³⁵¹ In this subgroup, each log unit increase in NT-proBNP was positively associated with the primary outcome (HR=1.59; 95% CI, 1.42 to 1.79).

NT-proBNP Levels Predicting All-Cause Mortality and Cardiovascular Morbidity

Table 28 describes study outcomes and followup period for articles assessing all-cause mortality and cardiovascular morbidity outcomes (n=26).

Table 28

Outcomes by length of time interval in stable population assessing all-cause mortality and cardiovascular morbidity for NT-proBNP.

Twenty-six publications^{4,277,278,289,291,292,301-303,305,306,309,316,320,322,323,325,326,330,335,337-339,341,354,356} measured composite outcomes relating to all-cause mortality and cardiovascular morbidity (Appendix J Table J-39). Two publications^4,330 did not report HRs or test statistics, so neither will be discussed further in this section. Five publications^{277,278,291,292,326} pertained to a single study in Scotland, two^306,320 involved a single study in Italy, and two^301,309 came from the CORONA study. The remaining papers reported on individual studies. For summarizing study characteristics and risk of bias, the publications^301,306,326 with the largest sample sizes were chosen to represent all of the Scottish, Italian, and CORONA papers. Thus, this section reports on 18 unique studies.

The included studies took place in medical settings (e.g., HF clinics). Proportions of males and mean ages ranged from 0.65³²³ to 0.88^303,339 and 49^303,337 to 72²⁸⁹ years. One paper³⁵⁶ did not report either characteristic. Another study³⁰⁵ reported proportions of males across three different strata based on tertiles of sACE2 plasma activity: 0.68, 0.73, and 0.89.³⁰⁵ Sample sizes ranged from 71³²² to 3,664;³⁰¹ mean sample size was 608. Lengths of followup were between six and 12 months for four publications,^{303,322,337,354} 13 to 24 months for 12 publications,^{277,278,289,291,292,320,323,325,326,335,338,339} and greater than 24 months for eight publications.^{301,302,305,306,309,316,341,356}

Four studies^{303,322,337,354} followed participants for between six and 12 months. A 658 person³⁰³ study with a mean followup of six months reported an adjusted HR=1.06 (95% CI, 1.03 to 1.08) per unit change in NT-proBNP. The outcome was all-cause mortality or urgent cardiac transplant. The other four studies reported a mean followup of 12 months. The largest (n=504) 12 month study³⁵⁴ employed an outcome of death, heart transplant, or HF hospitalization and found adjusted HRs (CIs) of 0.45 (0.45 to 1.46) and 2.43 (1.39 to 4.28) when NT-proBNP was measured at baseline and six months respectively. A 91 person study³³⁷ measuring all-cause mortality or worsening HF reported an adjusted HR=1.001 (p=0.036) for each one unit change in NT-proBNP. A study³²² examining all-cause mortality and HF hospitalization in 71 persons found no predictive value for NT-proBNP (HR=1.00; p=0.53).

Twelve publications^{277,278,289,291,292,320,323,325,326,335,338,339} reported 13- to 24- month followup periods. Five of these publications^{277,278,291,292,326} pertained to a single study in Scotland and two publications to a single study in Italy,^306,320 while the remaining five reports each covered individual studies.^{323,325,335,338,339}

The shortest followup in the 13 to 24 month category was a 13 month study³³⁸ of 210 persons; NT-proBNP values >581 pg/mL were associated with higher all-cause mortality, HF hospitalization, number of emergency department visits (HR=2.02; 95% CI, 1.08 to 3.78). A 17 month study³²⁵ of 290 participants evaluated log NT-proBNP in two separate multivariable regression models. This study found positive associations between each one-unit standard deviation increase in the peptide and a composite outcome of all-cause mortality, HF hospitalization, or urgent cardiac transplant (HR=1.9; 95% CI, 1.50 to 2.40 and adjusted HR=1.7; 95% CI, 1.30 to 2.30). Two 18 month studies also found positive associations between NT-proBNP and a composite outcome. The first study³³⁵ involved 82 persons who had a higher risk of death or HF hospitalization at an NT-proBNP cutpoint above 844 pg/mL (HR=4.50; 95% CI, 2.22 to 9.15). The second 18 month study³²³ recruited 166 persons and examined the same composite outcome; however, the authors only reported chi-square test statistics and p-values, so the magnitude of the positive association could not be assessed.

The five publications from the Scottish study^{277,278,291,292,326} reported on a rolling cohort of patients recruited between April 2001 and March 2004. Followups ranged from 13 to 22 months. The composite outcome was all-cause mortality or urgent cardiac transplant and multivariable regression analyses showed positive associations between higher NT-proBNP levels and incidences of the outcome. Since the analyses were repeated on an ever-increasing number of patients over time, median cutpoints varied in the publications. The last publication³²⁶ in this group reported a sample size of 182; NT-proBNP was positively associated with the outcome above 1,506 pg/mL (HR=2.7; 95% CI, 1.10 to 6.40).

The two publications from Italy appeared to include overlapping patients. The first study³²⁰ involved 142 patients followed for a mean of 20 months and the second³⁰⁶ contained 232 patients followed for a mean of 29 months. The combined outcome in both studies was all-cause mortality or HF hospitalization. Positive associations between peptide level and outcome were found in both studies. At a cutpoint ≥544 pg/mL, the adjusted HR=2.66 (1.24 to 5.71);³⁰⁶ at a cutpoint ≥3,283 pg/mL, the adjusted HR=2.16 (1.27 to 3.67).³²⁰

Two 24 month studies^289,339 also found positive associations between NT-proBNP levels and composite outcomes. An investigation of 546 persons³³⁹ found a one log unit increase in NT-proBNP to be associated with higher event rates for all-cause death or heart transplantation (HR=1.42; 95% CI, 1.19 to 1.71). An 88-person study²⁸⁹ only reported a chi-square test statistic and p-value for the positive association between NT-proBNP and all-cause death or HF rehospitalization.

Seven papers^{301,302,305,309,316,341,356} besides the second Italian publication³⁰⁶ reported followups between 25 and 60 months. Two papers^301,309 came from the CORONA study and the remaining four papers each pertained to an individual study. The CORONA papers reported on all-cause mortality or hospitalization for worsening HF at a mean of 32 months of followup. In both papers, each one-unit increase in log NT-proBNP was associated with increased mortality or hospitalization (HR=1.64 in both publications; 95% CI, 1.54 to 1.74 reported in one paper).³⁰⁹

The remaining five papers all contained results that were consistent with the above findings. A 30 month examination³¹⁶ of 149 participants found various permutations of NT-proBNP to be statistically significantly associated with all-cause mortality or heart transplant. Permutations included the risk per 100 pg/mL increase in NT-proBNP, as well as assessments at cutpoints of ≥760 pg/mL, ≥1,164 pg/mL, and ≥1,460 pg/mL. Adjusted HRs ranged from 1.07 to 15.85. A 34 month study³⁰⁵ of 113 participants investigated a three-pronged outcome of all-cause mortality, cardiac transplant, or HF hospitalization and found an adjusted HR=1.55 (95% CI, 1.01 to 2.33) in participants above a cutpoint of 1,240 pg/mL. The same three-pronged outcome was used in a 37 month study of 136 persons,³⁴¹ with an adjusted HR=2.12 (95% CI, 1.08 to 4.42) in persons at or above a cutpoint of 1,158 pg/mL. A 44 month investigation of 284 persons³⁰² found a non-significant higher risk of all-cause mortality or first hospitalization with each one-unit increase in NT-proBNP (HR=1.03; 95% CI, 1.00 to 1.06; p=0.099). In a large (n=3,480) 49 month study involving all-cause mortality or cardiovascular hospitalizations, the adjusted HR=1.46 (95% CI, 1.37 to 1.57) per log unit increase in NT-proBNP.

NT-proBNP Levels Predicting Cardiovascular Mortality and All-Cause Morbidity

Table 29 describes study outcomes and followup period for articles assessing cardiovascular mortality and all-cause morbidity outcomes (n=3).

Table 29

Outcomes by length of time interval in stable population assessing cardiovascular mortality and all-cause morbidity for NT-proBNP.

Three studies^293,343,356 investigated the composite outcome of cardiovascular mortality and all-cause morbidity (Appendix J Table J-40). Participants were persons with HF who were two-thirds male;^293,343 mean ages were 72³⁴³ or 57 years.²⁹³ In one study,³⁵⁶ the proportion of males and the mean age of participants was reported in two strata defined by a median NT-proBNP value of 339 pg/mL (below median: 37 percent, 70 years; above median: 41 percent, 74 years). Sample sizes were 106,³⁴³ 204,²⁹³ and 3,474.³⁵⁶ Mean followups were 16³⁴³ or 50³⁵⁶ months, or a median of 36 months.²⁹³ Mortality and morbidity were defined as cardiovascular/HF death and hospitalization in all three studies.

In all three studies, higher levels of NT-proBNP were positively associated with the composite outcome of mortality and hospitalization. Adjusted HRs (CIs) were 1.02 (1.01 to 1.03) per 100 pg/mL in the 16 month study,³⁴³ 1.28 (1.16 to 1.42) for NT-proBNP levels above 1,000 pg/mL in the median 36 month study,²⁹³ and 1.77 (1.43 to 2.20) for levels above 339 pg/mL in the large 50 month study.³⁵⁶ The 50 month study also reported other adjusted HRs: 1.44 (1.31 to 1.58) per log unit change in NT-proBNP; 1.13 (0.94 to 1.37) in the subgroup (n=1,737) with NT-proBNP >339 pg/mL; 0.57 (0.41 to 0.80) in the subgroup (n=1,737) with NT-proBNP <339 pg/mL. This study also found increasing point-estimate adjusted HRs for each quartile of NT-proBNP compared to the first quartile (Appendix J Table J-40).³⁵⁶

Design Characteristics of Studies

Six studies^364-369 investigated the prognostic value of baseline BNP in persons with HF who received some type of surgery or dialysis (Table 30, and Appendix J Table J-41). Five studies^364-368 were undertaken in stable HF populations and one study³⁶⁹ involved persons with acute decompensated HF. Surgeries included cardiac resynchronization therapy (CRT),^366-368 cardiac resynchronization defibrillator therapy (CRT-D),³⁶⁴ or noncardiac surgery (e.g., abdominal, orthopedic).³⁶⁵ One study³⁶⁹ involved peritoneal dialysis.

Table 30

Outcomes by length of time interval in surgical population assessing BNP.

Mean ages ranged from 61³⁶⁸ to 77 years.³⁶⁵ Percentages of males ranged from 41³⁶⁵ to 98 percent³⁶⁴ and mean lengths of followup ranged from 1³⁶⁵ to 18 months (Table 29, and Appendix J Table J-41).³⁶⁷ The smallest sample size was 32³⁶⁷ and the largest was 164.³⁶⁶ The mean sample size across all six studies was 87. Three studies used the Triage B-Type Natriuretic Peptide Test^364,366,369 and three used the ADVIA-Centaur immunoassay.^365,367,368

Risk of Bias

Overall risk of bias was low when the Hayden criteria were taken together for all of the studies (Figure 15, Appendix J Table J-41). Specific areas where risk of bias could be problematic included uncertainty over appropriate measuring of outcomes in four studies,^365-368 as well as inadequate measuring and accounting for confounders in five studies.^364-368

Figure 15

Risk of bias for prognostic surgical studies using the Hayden criteria assessing BNP. (a) source population clearly defined, (b) study population described c) study population represents source population, or population of interest (a) completeness of (more...)

Results

In stable HF populations, three studies^366-368 examined the prognostic value of BNP, measured at baseline, following CRT. In two studies,^366,367 effect sizes per unit change in BNP were close to unity. In one of these two studies, higher levels of BNP were associated with positive responses to CRT, (i.e., no HF hospitalization or improvement of at least 1 NYHA grade [95% CI, 1.001 to 1.003; p <0.01]).³⁶⁶ Conversely, in the second of these two studies, higher BNP levels were shown to be associated with HF hospitalization following CRT (adjusted HR=1.001; 95% CI, 1.000 to 1.002; p=0.024).³⁶⁷ In this second study,³⁶⁷ the authors found no association between higher BNP and all-cause mortality, although they did not provide numerical results to illustrate their finding. The last study³⁶⁸ involving CRT evaluated a composite outcome called HF progression, which included death, urgent transplant, HF hospitalization, or symptoms of HF progression. The adjusted HR per unit change in log BNP was 2.07 (95% CI, 1.19 to 3.62). See Appendix J Table J-42.

In the CRT-D study,³⁶⁴ persons with BNP levels at or above a cutpoint of 492 pg/mL had higher risks of all-cause mortality (adjusted HR=2.89; 95% CI, 1.06 to 7.88) or HF hospitalization (adjusted HR=4.23; 95% CI, 1.68 to 10.60).

The study evaluating the prognostic utility of BNP following noncardiac surgery reported a positive association between BNP levels and a composite outcome of all-cause mortality, acute coronary syndrome, or development/worsening HF.³⁶⁵ However, the authors reported a p-value (p=0.023), which does not show the magnitude of the association.

The lone study of 118 acute decompensated HF patients³⁶⁹ found a nonsignificant positive association between each one-unit change in BNP level and all-cause mortality following peritoneal dialysis (adjusted HR=1.38; 95% CI, 0.93 to 2.06).

Design Characteristics of Studies

Three papers^370-372 (Table 31 and Appendix J Table J-43) pertaining to two trials, TOPCARE-CHD,³⁷⁰ CARE-HF,^371,372 reported on the prognostic value of NT-proBNP following surgery in persons with stable HF. For TOPCARE-CHD,³⁷⁰ mean age was 62 years, 87% of participants were male, mean length of followup was 19 months, and sample size was 121 persons. The intervention under study was intracoronary infusion of bone marrow-derived mononuclear progenitor cells. NT-proBNP was measured using the Elecsys 2010.

Table 31

Outcomes by length of time interval in surgical population assessing NT-proBNP.

In the CARE-HF papers,^371,372 the age range was 55 to 75 years, 67% of participants were male, the median length of followup was 37.6 months, and 813 persons were studied. The intervention was cardiac resynchronization therapy and medical therapy compared to medical therapy alone. NT-proBNP was also measured using the Elecsys 2010.

Risk of Bias

Overall, risk of bias for the three publications was low (Figure 16, Appendix J Table J-43). However, a few specific questions on the Hayden instrument suggested potential issues with bias. Risk of bias was “uncertain” for appropriate measuring of outcomes in the case of all three articles. High risk of bias in the manner of measuring and accounting for confounders was possible in one paper.³⁷¹ One publication³⁷² was not designed to test the prognostic value of NT-proBNP.

Figure 16

Risk of bias for prognostic surgical studies using the Hayden criteria assessing NT-proBNP. (a) source population clearly defined, (b) study population described (c) study population represents source population, or population of interest (a) completeness (more...)

Results

In the TOPCARE-CHD paper,³⁷⁰ baseline NT-proBNP was shown to be positively associated with all-cause mortality. The adjusted hazard ratio was 7.2 (95% CI, 2.4 to 22.2) per one-unit increase in log NT-proBNP. All-cause mortality was also assessed in the CARE-HF papers: the adjusted HR for a one-unit increase in baseline log NT-proBNP was 1.56 (95% CI, 1.34 to 1.82);³⁷¹ the adjusted HR in a time-dependent model examining log NT-proBNP measured three months after randomization was 1.62 (95% CI, 1.41 to 1.85) per unit increase³⁷² (Table 31). See Appendix J Table J-44.

One of the CARE-HF papers³⁷¹ also examined the prognostic value of one-unit changes in baseline log NT-proBNP on sudden death (adjusted HR=1.33; 95% CI, 1.11 to 1.60) and death from pump failure (adjusted HR=1.92; 95% CI, 1.58 to 2.34).

Design Characteristics of Studies

Two publications^373,374 included both decompensated and stable HF patients in their study populations. Both are part of the same population prospectively recruited in a hospital in Pisa Italy, with one article³⁷³ assessing a sub-population of the other (Table 32 and Appendix J Table J-45).³⁷⁴

Table 32

Outcomes by length of time interval in both decompensated and stable population assessing NT-proBNP.

Risk of Bias

The risk of bias was assessed based on the Hayden criteria⁵⁸ as described in the methods section and Appendix E. Both articles^373,374 (Figure 17, Appendix J Table J-46) scored well on assessment of study participation, study attrition and prognostic factors. Both articles adequately measured and defined the study outcomes. However, since one publication³⁷³ used a composite outcome comprised of mortality and morbidity, it was rated low on the question asking whether “composite outcomes were avoided.” Both publications^373,374 failed to adequately measure and account for the important covariates, specified according to the a priori criteria set out (age, sex, body mass index and renal function). Analyses were appropriately conducted in both articles and both were adequately designed for prognostic study.^373,374

Figure 17

Risk of bias for prognostic studies using the Hayden criteria for both stable and decompensated population assessing NT-proBNP. (a) source population clearly defined, (b) study population described (c) study population represents source population, or (more...)

Results

Design Characteristics of Studies

From the five^{3,187,193,198,205} publications evaluating BNP in acute decompensated populations, only one recruited participants from emergency settings,³ while the other four recruited participants from among persons admitted to hospital.^{187,193,198,205} All BNP studies were cohort designs that included relatively equal proportions of men and women. One BNP study included only patients with NYHA class III and IV severity.¹⁸⁷ Sample sizes of BNP studies varied from 568 to 1,111 subjects. All studies evaluated BNP/NT-proBNP levels at admission and did not assess any serial or discharge from hospital levels.

Table 33 shows the outcomes and time intervals of studies who evaluated and presented data on incremental value of BNP/NT-proBNP. The studies evaluating the incremental value of BNP as a predictor evaluated only mortality related outcomes. Time intervals for outcome prediction varied from 3 months to 12 months in these studies the studies were undertaken in Greece,¹⁸⁷ Spain,^198,205 the United States,¹⁹³ and multinational settings.³ The assays used in these BNP studies included the Abbott AxSym,¹⁸⁷ the ELECSYS-proBNP,^3,205 the TRIAGE-BNP,¹⁹³ and the ADVIA-Centaur.¹⁹⁸ Other study characteristics are described in Appendix K Tables K-1 and K-2.

Table 33

Study outcomes and followup period for patients with decompensated heart failure.

Two studies evaluated NT-proBNP in patients with decompensated HF presenting to the emergency department in Spain²⁵¹ or admitted to hospital in Denmark.²⁵⁶ The Elecsys 2010 analyser assay was used in both studies to assess NT-proBNP levels. The mean age of the samples and proportion of males are described in Appendix K Table K-3.

Risk of Bias

Figure 18 (also Appendix K Table K-4) shows the distribution of risk of bias across the five BNP studies and single NT-proBNP study. Generally, these six publications were at low risk of bias. Studies tended to be problematic with respect to describing and accounting for confounders,^187,198,205 and with appropriate measurement of the outcome,^187,193,205 or unclear outcome measurement.^3,198

Figure 18

Risk of bias for studies using the Hayden criteria assessing BNP and NT-proBNP for population with decompensated HF. (a) source population clearly defined, (b) study population described (c) study population represents source population, or population (more...)

The single study that evaluated NT-proBNP in decompensated patients²⁵¹ was the only publication within that group that rated adequate for all criteria; however, this study also had the smallest sample size (n=107) of the studies with decompensated patients.

Results

Added Value of BNP to Prognostic Risk Prediction

There were no studies that evaluated the incremental value of adding BNP in chronic HF patients.

Added Value of NT-proBNP to Prognostic Risk Prediction

Fifteen publications^{283,286,301,306,309,320,329,340,344,349,353,357,360,373,376} evaluating patients with chronic stable HF considered the prognostic value of NT-proBNP.

Design Characteristics of Studies

The majority of these studies were publications based on related patient cohorts from Italy,^{306,320,349,373,376} from Spain,^353,357 from Europe,^340,344 and from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) with subjects recruited across Europe.^301,309 The remaining studies were conducted in Denmark,^283,329,360 and from multinational sites (16 countries).²⁸⁶

Three publications were based on randomized trials from the CORONA trial^301,309 and Valsartan Heart Failure Trial (Val-HeFT);²⁸⁶ both studies had large sample sizes ranging from 3,342 to 3,916. The remaining studies were prospective cohort designs and sample sizes varied from 107 to 891 subjects. All 15 studies used the ELECSYS -proBNP Immunoassay to evaluate the NT-proBNP.

Table 34 shows the length of followup and outcomes evaluated in the studies. The majority of studies evaluated mortality outcomes with fewer studies evaluating morbidity and composite outcomes. Appendix K Tables K-5 to K-8 detail the mean age and percentage of males for each estimate of incremental value of NT-proBNP.

Table 34

Study outcomes and followup period for patients with stable heart failure.

Risk of Bias

Figure 19 (also Appendix K Table K-9) shows the proportion of studies meeting various criteria assessed for risk of bias. Appendix E shows the individual study ratings for risk of bias. Almost all studies clearly defined their source of the population and this was representative of our target population. Similarly, all studies provided adequate description of their statistical analyses and used adequate designs to address this question of prognosis. Four of five related studies^{306,320,373,376} had problems with reporting which confounders were measured and how these were dealt with within the analysis, which accounted for the majority of studies with problems in this criteria.

Figure 19

Risk of bias for studies using the Hayden criteria assessing BNP and NT-proBNP for stable heart failure population. (a) source population clearly defined, (b) study population described (c) study population represents source population, or population (more...)

Results