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A systematic review of BNP as a predictor of prognosis in persons with coronary artery disease
Available online at www.sciencedirect.com
Clinical Biochemistry 41 (2008) 260 – 265
A systematic review of BNP as a predictor of prognosis in persons with coronary artery disease Mark Oremus a , Parminder S. Raina a,⁎, Pasqualina Santaguida a , Cynthia M. Balion b,c , Matthew J. McQueen b,c , Robert McKelvie e,f , Andrew Worster d,e , Lynda Booker a , Stephen A. Hill b,c a
McMaster Evidence-based Practice Center, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada b Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada c Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada d Division of Emergency Medicine, Department of Medicine, McMaster University, Hamilton, Ontario, Canada e Department of Medicine, McMaster University, Hamilton, Ontario, Canada f Division of Cardiology, Hamilton Health Sciences, Hamilton, Ontario, Canada Received 30 April 2007; received in revised form 21 August 2007; accepted 10 September 2007 Available online 25 September 2007
Abstract Objective: This systematic review was conducted to examine whether B-type natriuretic peptide (BNP) can predict mortality and other cardiac endpoints in persons diagnosed with coronary artery disease (CAD). Design and methods: Databases were searched from 1989 to February 2005 for primary studies that measured BNP for the purpose of diagnosis, prognosis, and monitoring treatment. Results: In 18 studies, concentrations of BNP were found to have consistent positive associations with poorer prognoses for persons with CAD. The overall range of effect (95% confidence interval) was 2.31 to 5.02, measured via a random effects meta-analysis on studies reporting an odds ratio. Prognostic ability was similar for mortality and non-fatal outcomes. Ranges of estimated measures of effect (i.e., odds ratio, relative risk, hazard ratio) were concentrated between 1.33 to 2.94 for mortality and 1.01 to 3.03 for non-fatal outcomes. Conclusions: Further research is needed to assess whether prognostic ability differs by comorbidity or concomitant treatment. As well, the importance and selection of cut points remains unresolved. Until greater clarity is given to these matters, it would be prudent for clinicians to employ caution when using concentrations of BNP to predict the prognosis of persons with CAD. © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: BNP; B-type natriuretic peptide; Coronary artery disease; Prognosis
Introduction B-type natriuretic peptide (BNP) has emerged as a promising prognostic indicator for persons with coronary artery disease (CAD). Several recent studies have reported that elevated BNP concentrations are associated with poorer CAD
⁎ Corresponding author. McMaster Evidence-based Practice Center, Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main St. W. DTC Room 308, Hamilton, ON, Canada L8N 1E9. Fax: +1 905 522 7681. E-mail address: [email protected] (P.S. Raina).
prognosis [1,2]. If this is so, then BNP could be a valuable means of identifying persons at risk for subsequent cardiac events [3]. As well, BNP could help identify persons who might benefit from interventions that prevent progression to more serious disease. This systematic review was conducted to investigate whether BNP can predict mortality and other cardiac endpoints in persons diagnosed with CAD. The review was part of a larger evidence report [4] commissioned by the Agency for Healthcare Research and Quality (AHRQ), United States Department of Health and Human Services. The AHRQ granted permission to publish the findings of the report.
0009-9120/$ - see front matter © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2007.09.011
M. Oremus et al. / Clinical Biochemistry 41 (2008) 260–265
Methods We searched MEDLINE, EMBASE, CINAHL, Cochrane Central, and AMED (Allied and Complementary Medicine) from January 1989, when the first assay for BNP was published, to February 2005. Keywords included natriuretic peptide, BNP, brain-type natriuretic peptide, BNP1-32, BNP32, BNP77-108, natriuretic factor-32, natriuretic peptide type-b, type-b natriuretic peptide, and ventricular natriuretic peptide. We included English language, comparative studies of human subjects, provided laboratory tests were performed on blood samples. Applicable study designs included randomized controlled trials (RCTs) and observational studies (cohort, case– control, and cross sectional). Study participants had to be ≥ 18 years of age with a diagnosis of CAD. We considered CAD to be the diagnosis if study authors wrote that participants had CAD, if participants were diagnosed with myocardial infarction (MI), acute coronary syndrome, or ischemia, or if participants reported chest pain or angina. We included studies with any type of outcome (e.g., mortality, recurrent angina). We excluded studies where participants had comorbid disorders such as heart transplant, renal disease, pulmonary embolism, cardiomyopathy, tumor, amyloid, leukemia, atrial fibrillation after pacemaker implant, respiratory disease, pulmonary hypertension, ischemic stroke, sepsis, or perimyocarditis. We restricted our interest to studies where BNP was measured with commercial assays and included Shionogi and Company (Osaka, Japan), Biosite (San Diego, CA), Bayer Diagnostics (Tarrytown., NY), Beckman Coulter (Fullerton, CA), and Abbott Laboratories (Abbott Park, IL). A team of trained reviewers independently screened all articles identified in the literature search. Two reviewers were required to reach consensus on article inclusion. We hypothesized a priori that the prognostic ability of BNP might differ by outcome (mortality/non-fatal [non-fatal includes one study [5] with a combination of mortality and non-fatal outcomes]). Therefore, we used ‘outcome’ as a stratum in our descriptive summary of the key findings of the included studies.
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v4.2.8 (The Nordic Cochrane Centre, Copenhagen, Denmark) was utilized to perform the meta-analysis. Results The literature search yielded 4338 citations. From these, 1733 citations (40%) proceeded to full text screening. Eighteen citations (1% of 1733) passed the full text screening phase and were included in the review (Fig. 1). All 18 citations (studies) were prospective cohorts [5,8–24]. Lengths of follow up varied greatly: 6 months or less in six studies [9,17,19,22–24], 7 to 12 months in six studies [5,10,11,14,18,21], 13 to 24 months in two studies [13,20], and more than 24 months in three studies [12,15,16]. Follow-up time was not reported in one study [8]. Other principal characteristics of the included studies are shown in Tables 1 and 2. Only 5 of the 18 studies [9,10,12,14,18] contained reports of whether participants were consecutively enrolled in the research. For blinding, reporting was only slightly better as seven of 18 studies [8,9,11,13,15,21,24] contained reports of whether outcomes were assessed in a blinded fashion. The lack of
Statistical analysis We conducted a meta-analysis to obtain an overall range of estimated effects. To have consistency between studies in the meta-analysis, we ran the analysis on the subset of included studies that reported an odds ratio (OR) and 95% confidence interval (CI), or that contained enough data to compute these estimates. Some studies reported multiple ORs, in which case we selected an OR according to the following algorithm: when there were multiple cut points, we chose the OR for the smallest cut point that was not a reference category; when there were multiple outcomes, we chose the OR for mortality; lastly, we took adjusted ORs before unadjusted ORs. The meta-analysis was conducted using a random effects model [6] weighted by the inverse variance of each effect estimate. Between-study heterogeneity was assessed with the I2 statistic [7]. A funnel plot was used to examine possible publication bias. Review Manager
Fig. 1. Flow diagram showing the number of citations processed at each level of the screening process.
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Table 1 Summary of BNP studies Study
n
Diagnosis
Method
Cut point (pg/mL)
Outcome
Result
MI, acute coronary syndrome
Triage®
100
All-cause mortality
aOR = 16.30 b
Chest pain, angina, MI
Triage®
80
Mortality
uOR = 2.94 b
ST segment elevation MI
ADVIA Centaur®
80
Mortality
aOR = 7.20 b
Miscellaneous electrocardiographic and laboratory data
Triage®
80
Mortality
aOR = 3.30 b
MI
Shionoria-IRMA
115.22
Mortality
Angina, eligibility for PCI, ischemia
Triage®
80
Mortality
aHR = 1.99 b uHR = 2.53 b aOR = 1.33 b, c
MI
Shionoria-IRMA
93.8–380.5
Left ventricular dysfunction
aOR = 1.01 b
Non-ST elevation acute coronary syndromes Angina
Triage®
80
Composite: death, MI, CHF
aHR = 2.10 b
Shionoria-IRMA
68
Recurrence of anginal attacks
uHR = 41.10 b
Triage®
80
Development of CHF or cardiogenic shock
aOR = 3.03 b
Age a Grabowski [9] 2004 Poland Jiang [10] 2004 China, Saudi Arabia Mega [22] 2004 USA Morrow [24] 2003 USA Omland [15] 1996 Scandinavia Wiviott [23] 2004 USA Bettencourt [14] 2000 Portugal Sabatine [5] 2002 USA Takase [12] 2004 Japan Wylie [11] 2004 USA
n: 126 Age: 58.8 y n: 949 Age: 52.5 y n: 438 Age range: 21–75 y n: 1676 Age range: 60–69 y n: 131 Age: 67.8 y n: 1865 Age range: 60–65 y n: 101 Age: 58.3 y n: 450 Age: NR n: 77 Age: 67 y n: 1124 Age: NR
Ischemic discomfort, documented coronary artery disease
aHR = adjusted hazard ratio; aOR = adjusted odds ratio; CAD = coronary artery disease; CHF = congestive heart failure; MI = = myocardial infarction; NR = not reported; PCI = percutaneous coronary intervention; uHR = unadjusted hazard ratio; uOR = unadjusted odds ratio; y = years. a Mean age if given in article. b Result statistically significant at 5% level. c aOR for women versus men (OR for men = 1.00).
reporting in both areas meant that it was impossible to rule out the presence of selection or information bias in a majority of the studies. BNP Cut points Cut points were used in most of the studies to quantitatively measure the prognostic ability of BNP. Fifteen studies [5,8– 13,15–17,19,21–24] used a single cut point and one [18] used multiple cut points. One study used a single cut point for analyses stratified by disease [14]. Cut points were not used in one study where post-bypass BNP concentrations were compared to interim clinical outcomes [20]. The cut points were based on the medians or quartiles of measured BNP in the study participants [8,11,15,21], ROC curves [9,12–14,16,18,22], previously published literature [5,10,17,23,24], or a regression analysis [19].
BNP There were six studies of BNP where the outcome was mortality [9,10,15,22–24] (Table 1). The point estimate measures of association in these studies ranged from 1.33 to 16.30, with most in the range of 1.33 to 2.94. There were four BNP studies with a non-fatal outcome or a combination of mortality and nonfatal outcomes [5,11,12,14]. The point estimate measure of association in one study with the non-fatal outcome of recurrent angina was 41.10 [12]; the measures of association in the other studies with non-fatal or combination outcomes ranged from 1.01 to 3.03 (Table 1). Other studies Table 2 shows the studies (n = 8) for which no numerical regression results were reported, or for which no regression analyses were performed.
Regression analyses in the included studies Meta-analysis Ten studies used regression analyses to examine the association between concentrations of BNP and the outcomes of interest (see Tables 1 and 2). Multiple regression was used in eight of these studies [5,9,11,14,15,22–24] and simple regression was used in two of these studies [10,12].
A total of six studies were included in the meta-analysis (Fig. 2) [9–11,22–24] and the prognostic effect ranged from 2.31 to 5.02 (95% CI). The I2 was 0%, indicating no heterogeneity between studies [7].
M. Oremus et al. / Clinical Biochemistry 41 (2008) 260–265
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Table 2 Summary of BNP studies in patients with CAD, no regression analyses or reported regression results Study
n
Diagnosis
Method
Cut point (pg/mL)
Outcome
Result
Coronary artery disease
Triage®
80
Death or re-infarction
NR
Coronary artery disease (multiple clinical diagnoses)
Triage®
120, 280, 385
NR
MI
Triage®
83
Intra- and post-operative cardiac events All-cause mortality
NR
Unstable angina, MI
Triage®
80
Mortality
NR
Ischemic discomfort
ShionoriaIRMA ShionoriaIRMA
80
Mortality
NR
450
(1) Pleural effusion (2) Atrial fibrillation
BNP of N450 pg/mL predicted the outcomes Univariate χ2 = 20.06 Multivariate χ2 = 7.003 NR
Age a Dokainish [8] 2005 USA Hutfless [18] 2004 USA
n: 895 Mean age: 57.3–60.6 y n: 98 Age: 63 y
Panteghini [13] 2003 Italy Sadanandan [21] 2004 USA Shimpo [17] 2004 USA Song [19] 2004 Japan
n: 92 Age: 52.5 y n: 276 Age: 61–67 y n: 810 Age: 58 y n: 40 Age range: 66.7–71.6 y
Suzuki [16] 2004 Japan
n: 145 Age: 64.7–66.7 y n: 14 Age: NR
Watanabe [20] 2003 Japan
New York Heart Association
MI
ShionoriaIRMA
180
Cardiac-related mortality
Elective CABG with cardiopulmonary bypass
ShionoriaIRMA
None
(1) Death (2) Angina
CABG = coronary artery bypass graft; CAD = coronary artery disease; MI = myocardial infarction; NR = not reported; y = years. a Mean age if given in article.
The funnel plot (Fig. 3) was asymmetric, thereby suggesting that the results of the meta-analysis may have been influenced by publication bias. This bias would have been less likely if the six study-specific odds ratios were symmetrically distributed around the summary odds ratio (i.e., 3.41) in the shape of an inverted funnel. Discussion Consistent positive associations were found between concentrations of BNP and outcomes reflecting poorer prognosis for persons with CAD. Most point estimate odds or hazard ratios, or relative risks, ranged from approximately 1.01 to 3.03 in the ten studies with regression results. The 95% CI obtained from the meta-analysis, albeit applicable to only 6 of the 18 included studies, suggested that the prognostic effect of BNP lies within a bound of 2.31 to 5.02, as measured by the OR. We
feel the magnitudes of these estimates overstate the true effect because studies with nonsignificant results are not always published. Additionally, all of the included studies were observational in nature, and these designs tend to produce larger effect estimates than RCTs [25]. The ranges of point estimates in the descriptive summary suggest that the prognostic effects of BNP are roughly the same for mortality and non-fatal (or non-fatal plus mortality) outcomes. Within the non-fatal outcome category, we could not ascertain whether the prognostic value of BNP was better for some non-fatal outcomes relative to others. This was due in part to different assay methods or varying means of diagnosing CAD or defining outcomes in the included studies. The meta-analysis indicated that there was no heterogeneity in six BNP studies, but we did not wish to place any emphasis on the single summary estimate of effect because the 12 studies that did not report ORs were omitted from the meta-analysis.
Fig. 2. Meta-analysis of BNP studies reporting an odds ratio. SE = standard error; CI = confidence interval.
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Conclusion The evidence from 18 studies indicates that concentrations of BNP are positively associated with poorer CAD prognosis. Further research is needed to identify whether the prognostic ability of BNP differs according to subpopulations defined by comorbidity or concomitant treatment. As well, the importance and selection of cut points remains unresolved. Until greater clarity is given to these matters, it would be prudent for clinicians to employ caution when using concentrations of BNP to predict the prognosis of persons with CAD. Acknowledgments Fig. 3. Funnel plot: Meta-analysis of BNP studies reporting an odds ratio.
We used the meta-analysis to obtain a range of effect (95% CI) to supplement the point estimates in our descriptive summary. This range was consistent with many of the point estimates. The funnel plot suggested the presence of publication bias. However, this bias could not be confirmed because asymmetrical plots can occur by chance when there are a small number of studies in the meta-analysis [26]. One central issue with many of the 18 included studies was a lack of control for comorbidity and ongoing treatment in regression analyses. Comorbidity is an important potential confounder because diseases such as diabetes or heart failure can affect B-type natriuretic peptide concentrations and the prognosis of CAD [4]. Ongoing treatment is also important, especially in the case of drugs that are used to treat CAD (e.g., ACE inhibitors [27]). In the eight studies (Table 2) with no regression analyses or no regression results, there was no means to assess the impact of either potential confounder. The situation was better in the 10 studies where the results of regression analyses were reported. The authors of eight of these studies controlled for comorbidity by including biological measures (e.g., ST-depression, CK MB level) or ‘previous disease’ variables (e.g., acute MI – yes, no) in their regression models. However, the authors of only one of these studies [23] controlled for ongoing treatment. Given the overall lack of control of confounding, we could not determine whether the prognostic effects of BNP differed in subpopulations defined by comorbidity or ongoing treatment [28]. There were no uniform data across studies to assess whether an optimal cut point existed or whether certain cut points were better predictors of some outcomes relative to others. Indeed, cut points may not be appropriate if risk increases with increasing concentrations of BNP. The strength of this systematic review is that it helps resolve the general question of whether BNP has prognostic value in persons diagnosed with CAD. Another strength is that our findings are consistent with studies that have been published since the February 2005 cut off date for our literature search. These more recent studies [28–35], published through November 2006, show that higher concentrations of BNP can predict the prognosis of CAD. These recent studies were also not uniform with respect to participants, diagnostic definitions, outcomes, and cut points.
Parminder Raina holds a Canadian Institute of Health Research Investigator award and an Ontario Premier’s Research Excellence award. This project was funded under Contract No. 290-02-0020 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services. References [1] Khan IA, Fink J, Nass C, Chen H, Christenson R, Defilippi CR. N-Terminal pro-B-type natriuretic peptide and B-type natriuretic peptide for identifying coronary artery disease and left ventricular hypertrophy in ambulatory chronic kidney disease patients. Am J Cardiol 2006;97:1530–4. [2] Doust JA, Pietrzak E, Dobson A, Glasziou P. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ 2005;330:625–33. [3] See R, de Lemos JA. Current status of risk stratification methods in acute coronary syndromes. Curr Cardiol Rep 2006;8:282–8. [4] Balion C, Santaguida P, Hill S, Worster A, McQueen M, Oremus M, et al. Testing for BNP and NT-proBNP in the diagnosis and prognosis of heart failure. AHRQ Publication No. 06-E014. Evidence Report/Technology Assessment: Number 142. Rockville, MD: Agency for Healthcare Research and Quality; 2006. [5] Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA, Rifai N, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, Creactive protein, and B-type natriuretic peptide. Circulation 2002;105: 1760–3. [6] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. [7] Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60. [8] Dokainish H, Pillai M, Murphy SA, DiBattiste PM, Schweiger MJ, Lotfi A, et al. Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy. J Am Coll Cardiol 2005;45:19–24. [9] Grabowski M, Filipiak KJ, Karpinski G, Wretowski D, Rdzanek A, Huczek Z, et al. Serum B-type natriuretic peptide levels on admission predict not only short-term death but also angiographic success of procedure in patients with acute ST-elevation myocardial infarction treated with primary angioplasty. Am Heart J 2004;148:655–62. [10] Jiang CY, Li N, Wang JA. Use of B-type natriuretic peptide in evaluation of early percutaneous coronary intervention in patients with acute coronary syndrome. Chin Med J 2004;117:1130–4. [11] Wylie JV, Murphy SA, Morrow DA, de Lemos JA, Antman EM, Cannon CP. Validated risk score predicts the development of congestive heart
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Clinical Biochemistry 41 (2008) 260 – 265
A systematic review of BNP as a predictor of prognosis in persons with coronary artery disease Mark Oremus a , Parminder S. Raina a,⁎, Pasqualina Santaguida a , Cynthia M. Balion b,c , Matthew J. McQueen b,c , Robert McKelvie e,f , Andrew Worster d,e , Lynda Booker a , Stephen A. Hill b,c a
McMaster Evidence-based Practice Center, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada b Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada c Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada d Division of Emergency Medicine, Department of Medicine, McMaster University, Hamilton, Ontario, Canada e Department of Medicine, McMaster University, Hamilton, Ontario, Canada f Division of Cardiology, Hamilton Health Sciences, Hamilton, Ontario, Canada Received 30 April 2007; received in revised form 21 August 2007; accepted 10 September 2007 Available online 25 September 2007
Abstract Objective: This systematic review was conducted to examine whether B-type natriuretic peptide (BNP) can predict mortality and other cardiac endpoints in persons diagnosed with coronary artery disease (CAD). Design and methods: Databases were searched from 1989 to February 2005 for primary studies that measured BNP for the purpose of diagnosis, prognosis, and monitoring treatment. Results: In 18 studies, concentrations of BNP were found to have consistent positive associations with poorer prognoses for persons with CAD. The overall range of effect (95% confidence interval) was 2.31 to 5.02, measured via a random effects meta-analysis on studies reporting an odds ratio. Prognostic ability was similar for mortality and non-fatal outcomes. Ranges of estimated measures of effect (i.e., odds ratio, relative risk, hazard ratio) were concentrated between 1.33 to 2.94 for mortality and 1.01 to 3.03 for non-fatal outcomes. Conclusions: Further research is needed to assess whether prognostic ability differs by comorbidity or concomitant treatment. As well, the importance and selection of cut points remains unresolved. Until greater clarity is given to these matters, it would be prudent for clinicians to employ caution when using concentrations of BNP to predict the prognosis of persons with CAD. © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: BNP; B-type natriuretic peptide; Coronary artery disease; Prognosis
Introduction B-type natriuretic peptide (BNP) has emerged as a promising prognostic indicator for persons with coronary artery disease (CAD). Several recent studies have reported that elevated BNP concentrations are associated with poorer CAD
⁎ Corresponding author. McMaster Evidence-based Practice Center, Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main St. W. DTC Room 308, Hamilton, ON, Canada L8N 1E9. Fax: +1 905 522 7681. E-mail address: [email protected] (P.S. Raina).
prognosis [1,2]. If this is so, then BNP could be a valuable means of identifying persons at risk for subsequent cardiac events [3]. As well, BNP could help identify persons who might benefit from interventions that prevent progression to more serious disease. This systematic review was conducted to investigate whether BNP can predict mortality and other cardiac endpoints in persons diagnosed with CAD. The review was part of a larger evidence report [4] commissioned by the Agency for Healthcare Research and Quality (AHRQ), United States Department of Health and Human Services. The AHRQ granted permission to publish the findings of the report.
0009-9120/$ - see front matter © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2007.09.011
M. Oremus et al. / Clinical Biochemistry 41 (2008) 260–265
Methods We searched MEDLINE, EMBASE, CINAHL, Cochrane Central, and AMED (Allied and Complementary Medicine) from January 1989, when the first assay for BNP was published, to February 2005. Keywords included natriuretic peptide, BNP, brain-type natriuretic peptide, BNP1-32, BNP32, BNP77-108, natriuretic factor-32, natriuretic peptide type-b, type-b natriuretic peptide, and ventricular natriuretic peptide. We included English language, comparative studies of human subjects, provided laboratory tests were performed on blood samples. Applicable study designs included randomized controlled trials (RCTs) and observational studies (cohort, case– control, and cross sectional). Study participants had to be ≥ 18 years of age with a diagnosis of CAD. We considered CAD to be the diagnosis if study authors wrote that participants had CAD, if participants were diagnosed with myocardial infarction (MI), acute coronary syndrome, or ischemia, or if participants reported chest pain or angina. We included studies with any type of outcome (e.g., mortality, recurrent angina). We excluded studies where participants had comorbid disorders such as heart transplant, renal disease, pulmonary embolism, cardiomyopathy, tumor, amyloid, leukemia, atrial fibrillation after pacemaker implant, respiratory disease, pulmonary hypertension, ischemic stroke, sepsis, or perimyocarditis. We restricted our interest to studies where BNP was measured with commercial assays and included Shionogi and Company (Osaka, Japan), Biosite (San Diego, CA), Bayer Diagnostics (Tarrytown., NY), Beckman Coulter (Fullerton, CA), and Abbott Laboratories (Abbott Park, IL). A team of trained reviewers independently screened all articles identified in the literature search. Two reviewers were required to reach consensus on article inclusion. We hypothesized a priori that the prognostic ability of BNP might differ by outcome (mortality/non-fatal [non-fatal includes one study [5] with a combination of mortality and non-fatal outcomes]). Therefore, we used ‘outcome’ as a stratum in our descriptive summary of the key findings of the included studies.
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v4.2.8 (The Nordic Cochrane Centre, Copenhagen, Denmark) was utilized to perform the meta-analysis. Results The literature search yielded 4338 citations. From these, 1733 citations (40%) proceeded to full text screening. Eighteen citations (1% of 1733) passed the full text screening phase and were included in the review (Fig. 1). All 18 citations (studies) were prospective cohorts [5,8–24]. Lengths of follow up varied greatly: 6 months or less in six studies [9,17,19,22–24], 7 to 12 months in six studies [5,10,11,14,18,21], 13 to 24 months in two studies [13,20], and more than 24 months in three studies [12,15,16]. Follow-up time was not reported in one study [8]. Other principal characteristics of the included studies are shown in Tables 1 and 2. Only 5 of the 18 studies [9,10,12,14,18] contained reports of whether participants were consecutively enrolled in the research. For blinding, reporting was only slightly better as seven of 18 studies [8,9,11,13,15,21,24] contained reports of whether outcomes were assessed in a blinded fashion. The lack of
Statistical analysis We conducted a meta-analysis to obtain an overall range of estimated effects. To have consistency between studies in the meta-analysis, we ran the analysis on the subset of included studies that reported an odds ratio (OR) and 95% confidence interval (CI), or that contained enough data to compute these estimates. Some studies reported multiple ORs, in which case we selected an OR according to the following algorithm: when there were multiple cut points, we chose the OR for the smallest cut point that was not a reference category; when there were multiple outcomes, we chose the OR for mortality; lastly, we took adjusted ORs before unadjusted ORs. The meta-analysis was conducted using a random effects model [6] weighted by the inverse variance of each effect estimate. Between-study heterogeneity was assessed with the I2 statistic [7]. A funnel plot was used to examine possible publication bias. Review Manager
Fig. 1. Flow diagram showing the number of citations processed at each level of the screening process.
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Table 1 Summary of BNP studies Study
n
Diagnosis
Method
Cut point (pg/mL)
Outcome
Result
MI, acute coronary syndrome
Triage®
100
All-cause mortality
aOR = 16.30 b
Chest pain, angina, MI
Triage®
80
Mortality
uOR = 2.94 b
ST segment elevation MI
ADVIA Centaur®
80
Mortality
aOR = 7.20 b
Miscellaneous electrocardiographic and laboratory data
Triage®
80
Mortality
aOR = 3.30 b
MI
Shionoria-IRMA
115.22
Mortality
Angina, eligibility for PCI, ischemia
Triage®
80
Mortality
aHR = 1.99 b uHR = 2.53 b aOR = 1.33 b, c
MI
Shionoria-IRMA
93.8–380.5
Left ventricular dysfunction
aOR = 1.01 b
Non-ST elevation acute coronary syndromes Angina
Triage®
80
Composite: death, MI, CHF
aHR = 2.10 b
Shionoria-IRMA
68
Recurrence of anginal attacks
uHR = 41.10 b
Triage®
80
Development of CHF or cardiogenic shock
aOR = 3.03 b
Age a Grabowski [9] 2004 Poland Jiang [10] 2004 China, Saudi Arabia Mega [22] 2004 USA Morrow [24] 2003 USA Omland [15] 1996 Scandinavia Wiviott [23] 2004 USA Bettencourt [14] 2000 Portugal Sabatine [5] 2002 USA Takase [12] 2004 Japan Wylie [11] 2004 USA
n: 126 Age: 58.8 y n: 949 Age: 52.5 y n: 438 Age range: 21–75 y n: 1676 Age range: 60–69 y n: 131 Age: 67.8 y n: 1865 Age range: 60–65 y n: 101 Age: 58.3 y n: 450 Age: NR n: 77 Age: 67 y n: 1124 Age: NR
Ischemic discomfort, documented coronary artery disease
aHR = adjusted hazard ratio; aOR = adjusted odds ratio; CAD = coronary artery disease; CHF = congestive heart failure; MI = = myocardial infarction; NR = not reported; PCI = percutaneous coronary intervention; uHR = unadjusted hazard ratio; uOR = unadjusted odds ratio; y = years. a Mean age if given in article. b Result statistically significant at 5% level. c aOR for women versus men (OR for men = 1.00).
reporting in both areas meant that it was impossible to rule out the presence of selection or information bias in a majority of the studies. BNP Cut points Cut points were used in most of the studies to quantitatively measure the prognostic ability of BNP. Fifteen studies [5,8– 13,15–17,19,21–24] used a single cut point and one [18] used multiple cut points. One study used a single cut point for analyses stratified by disease [14]. Cut points were not used in one study where post-bypass BNP concentrations were compared to interim clinical outcomes [20]. The cut points were based on the medians or quartiles of measured BNP in the study participants [8,11,15,21], ROC curves [9,12–14,16,18,22], previously published literature [5,10,17,23,24], or a regression analysis [19].
BNP There were six studies of BNP where the outcome was mortality [9,10,15,22–24] (Table 1). The point estimate measures of association in these studies ranged from 1.33 to 16.30, with most in the range of 1.33 to 2.94. There were four BNP studies with a non-fatal outcome or a combination of mortality and nonfatal outcomes [5,11,12,14]. The point estimate measure of association in one study with the non-fatal outcome of recurrent angina was 41.10 [12]; the measures of association in the other studies with non-fatal or combination outcomes ranged from 1.01 to 3.03 (Table 1). Other studies Table 2 shows the studies (n = 8) for which no numerical regression results were reported, or for which no regression analyses were performed.
Regression analyses in the included studies Meta-analysis Ten studies used regression analyses to examine the association between concentrations of BNP and the outcomes of interest (see Tables 1 and 2). Multiple regression was used in eight of these studies [5,9,11,14,15,22–24] and simple regression was used in two of these studies [10,12].
A total of six studies were included in the meta-analysis (Fig. 2) [9–11,22–24] and the prognostic effect ranged from 2.31 to 5.02 (95% CI). The I2 was 0%, indicating no heterogeneity between studies [7].
M. Oremus et al. / Clinical Biochemistry 41 (2008) 260–265
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Table 2 Summary of BNP studies in patients with CAD, no regression analyses or reported regression results Study
n
Diagnosis
Method
Cut point (pg/mL)
Outcome
Result
Coronary artery disease
Triage®
80
Death or re-infarction
NR
Coronary artery disease (multiple clinical diagnoses)
Triage®
120, 280, 385
NR
MI
Triage®
83
Intra- and post-operative cardiac events All-cause mortality
NR
Unstable angina, MI
Triage®
80
Mortality
NR
Ischemic discomfort
ShionoriaIRMA ShionoriaIRMA
80
Mortality
NR
450
(1) Pleural effusion (2) Atrial fibrillation
BNP of N450 pg/mL predicted the outcomes Univariate χ2 = 20.06 Multivariate χ2 = 7.003 NR
Age a Dokainish [8] 2005 USA Hutfless [18] 2004 USA
n: 895 Mean age: 57.3–60.6 y n: 98 Age: 63 y
Panteghini [13] 2003 Italy Sadanandan [21] 2004 USA Shimpo [17] 2004 USA Song [19] 2004 Japan
n: 92 Age: 52.5 y n: 276 Age: 61–67 y n: 810 Age: 58 y n: 40 Age range: 66.7–71.6 y
Suzuki [16] 2004 Japan
n: 145 Age: 64.7–66.7 y n: 14 Age: NR
Watanabe [20] 2003 Japan
New York Heart Association
MI
ShionoriaIRMA
180
Cardiac-related mortality
Elective CABG with cardiopulmonary bypass
ShionoriaIRMA
None
(1) Death (2) Angina
CABG = coronary artery bypass graft; CAD = coronary artery disease; MI = myocardial infarction; NR = not reported; y = years. a Mean age if given in article.
The funnel plot (Fig. 3) was asymmetric, thereby suggesting that the results of the meta-analysis may have been influenced by publication bias. This bias would have been less likely if the six study-specific odds ratios were symmetrically distributed around the summary odds ratio (i.e., 3.41) in the shape of an inverted funnel. Discussion Consistent positive associations were found between concentrations of BNP and outcomes reflecting poorer prognosis for persons with CAD. Most point estimate odds or hazard ratios, or relative risks, ranged from approximately 1.01 to 3.03 in the ten studies with regression results. The 95% CI obtained from the meta-analysis, albeit applicable to only 6 of the 18 included studies, suggested that the prognostic effect of BNP lies within a bound of 2.31 to 5.02, as measured by the OR. We
feel the magnitudes of these estimates overstate the true effect because studies with nonsignificant results are not always published. Additionally, all of the included studies were observational in nature, and these designs tend to produce larger effect estimates than RCTs [25]. The ranges of point estimates in the descriptive summary suggest that the prognostic effects of BNP are roughly the same for mortality and non-fatal (or non-fatal plus mortality) outcomes. Within the non-fatal outcome category, we could not ascertain whether the prognostic value of BNP was better for some non-fatal outcomes relative to others. This was due in part to different assay methods or varying means of diagnosing CAD or defining outcomes in the included studies. The meta-analysis indicated that there was no heterogeneity in six BNP studies, but we did not wish to place any emphasis on the single summary estimate of effect because the 12 studies that did not report ORs were omitted from the meta-analysis.
Fig. 2. Meta-analysis of BNP studies reporting an odds ratio. SE = standard error; CI = confidence interval.
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Conclusion The evidence from 18 studies indicates that concentrations of BNP are positively associated with poorer CAD prognosis. Further research is needed to identify whether the prognostic ability of BNP differs according to subpopulations defined by comorbidity or concomitant treatment. As well, the importance and selection of cut points remains unresolved. Until greater clarity is given to these matters, it would be prudent for clinicians to employ caution when using concentrations of BNP to predict the prognosis of persons with CAD. Acknowledgments Fig. 3. Funnel plot: Meta-analysis of BNP studies reporting an odds ratio.
We used the meta-analysis to obtain a range of effect (95% CI) to supplement the point estimates in our descriptive summary. This range was consistent with many of the point estimates. The funnel plot suggested the presence of publication bias. However, this bias could not be confirmed because asymmetrical plots can occur by chance when there are a small number of studies in the meta-analysis [26]. One central issue with many of the 18 included studies was a lack of control for comorbidity and ongoing treatment in regression analyses. Comorbidity is an important potential confounder because diseases such as diabetes or heart failure can affect B-type natriuretic peptide concentrations and the prognosis of CAD [4]. Ongoing treatment is also important, especially in the case of drugs that are used to treat CAD (e.g., ACE inhibitors [27]). In the eight studies (Table 2) with no regression analyses or no regression results, there was no means to assess the impact of either potential confounder. The situation was better in the 10 studies where the results of regression analyses were reported. The authors of eight of these studies controlled for comorbidity by including biological measures (e.g., ST-depression, CK MB level) or ‘previous disease’ variables (e.g., acute MI – yes, no) in their regression models. However, the authors of only one of these studies [23] controlled for ongoing treatment. Given the overall lack of control of confounding, we could not determine whether the prognostic effects of BNP differed in subpopulations defined by comorbidity or ongoing treatment [28]. There were no uniform data across studies to assess whether an optimal cut point existed or whether certain cut points were better predictors of some outcomes relative to others. Indeed, cut points may not be appropriate if risk increases with increasing concentrations of BNP. The strength of this systematic review is that it helps resolve the general question of whether BNP has prognostic value in persons diagnosed with CAD. Another strength is that our findings are consistent with studies that have been published since the February 2005 cut off date for our literature search. These more recent studies [28–35], published through November 2006, show that higher concentrations of BNP can predict the prognosis of CAD. These recent studies were also not uniform with respect to participants, diagnostic definitions, outcomes, and cut points.
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