CLINICAL RESEARCH: HEART FAILURE
Gender-Specific Risk Stratification With B-Type Natriuretic Peptide Levels in Patients With Acute Dyspnea
Insights From the B-type Natriuretic Peptide for Acute Shortness of Breath Evaluation Study
Michael Christ, MD*,
Kirsten Laule-Kilian, BSc,
Willibald Hochholzer, MD,
Theresia Klima, MD,
Tobias Breidthardt, MD,
Andre P. Perruchoud, MD and
Christian Mueller, MD
Department of Internal Medicine, Medical Division A, University Hospital, Basel, Switzerland
Manuscript received April 3, 2006;
revised manuscript received July 5, 2006,
accepted July 17, 2006.
* Reprint requests and correspondence: Dr. Michael Christ, Medical Division A, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. (Email: MicChrist{at}uhbs.ch).
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Abstract
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OBJECTIVES: We examined whether B-type natriuretic peptide (BNP) levels allow gender-specific risk stratification in patients with acute dyspnea.
BACKGROUND: B-type natriuretic peptide levels determined in patients with heart failure correlate with the severity of disease and prognosis. Gender differences in risk prediction are poorly examined.
METHODS: The BASEL (B-type natriuretic peptide for Acute Shortness of Breath Evaluation) Study enrolled 190 female and 262 male patients presenting with acute dyspnea.
RESULTS: At 24 months, cumulative mortality was comparable in women and men (38% vs. 35%, p = 0.66). Cox regression analyses revealed that BNP levels >500 pg/ml indicated a 5.1-fold increase in mortality for women (95% confidence interval [CI] 3.0 to 8.5, p < 0.001) versus a 1.8-fold increase in men (95% CI 1.2 to 2.6; p = 0.007). The area under the receiver-operating characteristic curve (AUC) for BNP to predict death was significantly higher in female (AUC: 0.80, 95% CI 0.73 to 0.86) than in male patients (AUC: 0.64, 95% CI 0.57 to 0.71; p = 0.001 for the comparison of AUCwomen versus AUCmen). Women with BNP >500 pg/ml displayed a higher mortality as compared with men with BNP >500 pg/ml (68% vs. 46%, p = 0.015). Interaction analysis showed that BNP is a stronger predictor of death in women than in men (p = 0.008).
CONCLUSIONS: B-type natriuretic peptide plasma levels seem to be stronger predictors of death in women than in men.
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Abbreviations and Acronyms
| | AUC = area under the (receiver-operating characteristic) curve | | BNP = B-type natriuretic peptide | | CI = confidence interval | | HF = heart failure |
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B-type natriuretic peptide (BNP) is an important biomarker to diagnose heart failure (HF) in patients presenting with acute dyspnea to the emergency department (1). In this setting, the use of BNP improves patient management and is cost-effective (2). B-type natriuretic peptide plasma levels are not only useful to diagnose HF but also to predict morbidity and mortality in chronic HF (3).
Important gender differences in HF patients have been reported (4). Women more likely develop HF after acute myocardial infarction (5), and women with acute HF have less improvement in physical health status during follow-up and a lower perceived quality of care than men (6). We examined whether BNP plasma levels allow gender-specific risk stratification in patients with acute dyspnea.
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Methods
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Setting and study population.
A total of 452 consecutive patients presenting with acute dyspnea were enrolled in the BASEL (B-type natriuretic peptide for Acute Shortness of Breath Evaluation) study (2). The study was approved by the institutional review board and conducted according to the principles of good clinical practice. Patients with severe renal disease (serum creatinine >250 µmol/l) or cardiogenic shock were excluded.
Clinical and laboratory assessment.
Clinical assessment including determination of a final discharge diagnosis was performed in all patients. B-type natriuretic peptide was measured with the use of a rapid fluorescence immunoassay (Biosite Inc., San Diego, California) (7). B-type natriuretic peptide levels were available for the diagnosis in one-half of presenting patients and determined in a blinded fashion in the other half of patients (2).
End points and follow-up.
The primary end point of this analysis was all-cause mortality related to BNP levels in women and men. Each patient was contacted via telephone by a single trained researcher at specified intervals. If necessary, referring physicians were contacted regarding a patient's premorbid health status, or the administrative databases of respective hometowns were reviewed.
Statistical analysis.
Patients were grouped with prospectively defined and established BNP cutoff points (low: <100 pg/ml; intermediate: 100 to 500 pg/ml; high: >500 pg/ml). Cox proportional hazard models were used to evaluate the associations between outcome measures. Event-free survival was estimated with the Kaplan-Meier method. A receiver-operating characteristic curve was constructed to assess BNP as a predictor of mortality. All p values reported are 2-sided, and a p value <0.05 was considered significant. All statistical calculations were performed with the SPSS statistical software package (version 13.0; SPSS Inc., Chicago, Illinois).
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Results
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Patient characteristics are presented in Table 1. At 24 months, cumulative mortality was comparable in women and men (38% vs. 35%, p = 0.66) (Figure 1). In the study cohort, no significant difference in plasma BNP levels was observed between genders (Table 1). However, BNP levels were significantly higher in women (median: 835, interquartile range: 440 to 1,300 pg/ml) than in men (median: 459, interquartile range: 134 to 1,300 pg/ml; p = 0.005) who died. Results of univariate Cox regression analyses are displayed in Table 2. Cox regression analyses revealed that risk of death was 5.1-fold higher (95% confidence interval [CI] 3.0 to 8.5, p < 0.001) in women with BNP levels >500 pg/ml compared with women with BNP  500 pg/ml. Risk of death was 1.8-fold higher in men with BNP >500 pg/ml compared with men with BNP 500 pg/ml (95% CI 1.2 to 2.6; p = 0.007). Survival in patients with BNP >500 pg/ml was significantly worse for women than men (Figure 2). The area under the receiver-operating characteristic curve (AUC) for BNP to predict death was significantly greater for women than men (p = 0.001) (Figure 3).
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Figure 3 Receiver-operating characteristic curves analyzing the ability of B-type natriuretic peptide (BNP) levels to predict death in women and men. Area under the receiver operating characteristics curve (AUC) with 95% confidence intervals (CI) are given.
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B-type natriuretic peptide levels, in addition to body mass index and age, significantly contributed to multivariate Cox regression models indicating increased risk of death in women (Table 3). B-type natriuretic peptide plasma levels did not independently predict death in men. Interaction analysis showed that risk prediction with BNP is dependent on gender and BNP is a stronger predictor of risk of death in women than in men (p = 0.008). The BNP levels were weakly associated with age (r2 = 0.06 for women, p < 0.001; r2 = 0.02 for men, p = 0.07). In addition, negative linear associations with body mass index (r2 = 0.09 for women, p < 0.001; r2 = 0.1 for men, p < 0.001) and renal function (r2 = 0.21 for women, p < 0.001; r2 = 0.20 for men, p < 0.001) were found.
Resource use (p = 0.81 for hospital stay; p = 0.27 for transfer to intensive care unit) and discharge medication was comparable in women and men. Echocardiography was performed in 48% of women and 51% of men (p = 0.57). At discharge, angiotensin-converting enzyme (ACE) inhibitors (p = 0.55) and beta-blockers (p = 0.92) were prescribed similarly for women and men. An exploratory analysis showed that gender-differences in risk prediction are particularly evident in patients with cardiac dyspnea (Figure 4).
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Figure 4 Survival in women and men with B-type natriuretic peptide (BNP) levels >500 pg/ml and cardiac (left) or non-cardiac (right) causes of acute dyspnea (log-rank test for comparison of curves).
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Discussion
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The present study examined whether increased BNP plasma levels are equally useful in the risk stratification of women and men presenting with acute dyspnea to the emergency department. The main results are the following: 1) patients presenting with acute dyspnea displayed a high mortality rate independent of gender, 2) women with BNP levels >500 pg/ml had significantly higher mortality than men with BNP levels >500 pg/ml, 3) BNP levels were significant independent predictors of death in women but not in men, and 4) receiver operating characteristics and interaction analysis confirmed that BNP levels were stronger predictors of death in women than in men.
Elevated BNP levels in patients with acute dyspnea indicate poor prognosis, thus extending data obtained in patients with chronic (3) or acute HF after 6 months of follow-up (8). Previous data suggest that levels of natriuretic peptides in women are in excess of that in men with comparable symptom and disease severity. Subsequently, it has been suggested to use higher BNP cutoff levels for the diagnosis and management of HF in women (9). Our findings in patients presenting with acute dyspnea demonstrate that increased BNP levels are associated with an excess risk of death to a greater extent in women than in men. Possibly owing to the high prevalence of diastolic HF, HF severity might be underestimated by noninvasive diagnostic tests in women. This could potentially lead to underuse of appropriate HF treatment (10).
Our data suggest that BNP might be a more appropriate test to estimate severity of cardiac disease in women, whereas other diagnostic measures might be more useful for risk prediction in men. It is tempting to speculate whether BNP formation and release might be regulated gender-specifically. Indeed, sex hormones interact with regulation of neurohormones including natriuretic peptides (11).
Study limitations.
First, we prospectively decided to record all-cause mortality because classification of death in clinical practice is inaccurate, challenging, and might lead to questionable conclusions. However, detailed information regarding causes of death might have provided additional insights. Second, this is a post hoc analysis of a moderate-sized randomized controlled study. Therefore, our findings need to be confirmed by additional studies before definite conclusions regarding gender-specific risk prediction in general and optimal cutoff values in particular can be made.
Conclusions.
Patients presenting with acute dyspnea to the emergency department display poor particular prognosis independent of gender. B-type natriuretic peptide plasma levels seem to be stronger predictors of death in women than in men.
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Acknowledgments
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The authors kindly appreciate the help of Andrew Rosser, MD, for proofreading the manuscript.
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Footnotes
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This study was supported by research grants from the Swiss National Science Foundation (PP00B-102853), the Swiss Heart Foundation, and the Novartis Foundation (to Dr. Mueller).
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References
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1. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure N Engl J Med 2002;347:161-167.[Abstract/Free Full Text]2. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea N Engl J Med 2004;350:647-654.[Abstract/Free Full Text] 3. 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.[Abstract/Free Full Text] 4. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure JAMA 1996;275:1557-1562.[Abstract/Free Full Text] 5. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex-based differences in early mortality after myocardial infarctionNational Registry of Myocardial Infarction 2 Participants. N Engl J Med 1999;341:217-225.[Abstract/Free Full Text] 6. Chin MH, Goldman L. Gender differences in 1-year survival and quality of life among patients admitted with congestive heart failure Med Care 1998;36:1033-1046.[CrossRef][Web of Science][Medline] 7. Cheng V, Kazanagra R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study J Am Coll Cardiol 2001;37:386-391.[Abstract/Free Full Text] 8. Harrison A, Morrison LK, Krishnaswamy P, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea Ann Emerg Med 2002;39:131-138.[CrossRef][Web of Science][Medline] 9. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett Jr JC. Plasma brain natriuretic peptide concentration: impact of age and gender J Am Coll Cardiol 2002;40:976-982.[Abstract/Free Full Text] 10. Komajda M, Follath F, Swedberg K, et al. The EuroHeart Failure Survey programme—a survey on the quality of care among patients with heart failure in EuropePart 2: treatment. Eur Heart J 2003;24:464-474.[Abstract/Free Full Text] 11. Clerico A, Recchia FA, Passino C, Emdin M. Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications Am J Physiol Heart Circ Physiol 2006;290:H17-H29.[Abstract/Free Full Text]
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