Role of BNP levels on the prognosis of decompensated advanced heart failure

Abstracts

FUNDAMENTO: A insuficiência cardíaca (IC) é doença que cursa com má evolução, especialmente naqueles com IC avançada. A dosagem de peptídeo natriurético tipo B(BNP), ao lado da utilidade no diagnóstico da descompensação cardíaca, vem se mostrando útil na avaliação prognóstica. OBJETIVOS: Verificar se os níveis de BNP identificam quais pacientes evoluiriam pior e se o BNP seria fator independente de mortalidade considerando-se idade, sexo, funções cardíaca e renal e etiologia da cardiopatia. MÉTODOS: 189 pacientes com IC avançada em classe funcional III/IV foram estudados. Todos tinham disfunção sistólica e dosaram-se os níveis de BNP na hospitalização. Analisaram-se as variáveis relacionadas com a mortalidade através de análises univariada e multivariada. RESULTADOS: Os níveis de BNP foram mais elevados nos pacientes que morreram no primeiro ano de seguimento (1.861,9 versus 1.408,1 pg/dL; p = 0,044) e nos chagásicos (1.985 versus 1.452 pg/mL; p = 0,001), e esses pacientes chagásicos tiveram maior mortalidade no primeiro ano de seguimento (56% versus 35%; p = 0,010). Pela curva ROC, o valor de BNP de 1.400 pg/mL foi o melhor preditor de eventos, estando os valores elevados associados a FEVE mais baixa (0,23 versus 0,28; p = 0,002) e maior grau de disfunção renal (ureia média 92 versus 74,5 mg/dL; p = 0,002). CONCLUSÃO: Na IC avançada, os níveis elevados de BNP identificam pacientes com maior potencial de pior evolução. Os pacientes chagásicos apresentam níveis mais elevados de BNP do que as outras etiologias e têm pior evolução.

Insuficiência Cardíaca; Peptídeos Natriuréticos; Prognóstico; Sobrevida

ORIGINAL ARTICLE

Hospital Auxiliar de Cotoxó - Instituto do Coração - HC FMUSP, São Paulo, SP - Brasil

Mailing Address

ABSTRACT

BACKGROUND: Heart failure (HF) is a condition with poor outcome, especially in advanced cases. Determination of B-type natriuretic peptide (BNP) levels is useful in the diagnosis of cardiac decompensation and has also been proving useful in the prognostic evaluation.

OBJECTIVES: To verify whether BNP levels are able to identify patients with a poorer outcome and whether it is an independent prognostic factor considering age, gender, cardiac and renal functions, as well as the cause of heart disease.

METHODS: 189 patients in functional class III/IV advanced HF were studied. All had systolic dysfunction and had their BNP levels determined during hospitalization. Variables related to mortality were studied using univariate and multivariate analyses.

RESULTS: BNP levels were higher in patients who died in the first year of follow-up (1,861.9 versus 1,408.1 pg/dL; p = 0.044) and in chagasic patients (1,985 versus 1,452 pg/mL; p = 0.001); the latter had a higher mortality rate in the first year of follow-up (56% versus 35%; p = 0.010). The ROC curve analysis showed that the BNP level of 1,400 pg/mL was the best predictor of events; high levels were associated with lower LVEF (0.23 versus 0.28; p = 0.002) and more severe degree of renal dysfunction (mean urea 92 versus 74.5 mg/dL; p = 0.002).

CONCLUSION: In advanced HF, high BNP levels identified patients at higher risk of a poorer outcome. Chagasic patients showed higher BNP levels than those with heart diseases of other causes, and have poorer prognosis.

Keywords: Heart Failure; Natriuretic Peptides; Prognosis; Survivorship (Public Health).

Introduction

HF is a condition known to have a poor prognosis, with significant reduction in the quality of life, increased hospitalization rates, and reduced life expectancy, especially in advanced cases¹.

Innumerable clinical and laboratorial data help identify patients with a potentially poorer outcome². BNP determination is useful in the diagnosis of cardiac decompensation and has also been proven useful in the prognostic evaluation; in addition, it is a non-subjective variable^3-6. The higher the peptide levels, the worse the patient's outcome, the longer the length of hospital stay, and the higher the mortality rate^2,3. However, BNP levels are under the influence not only of the patient's functional status, but also of factors such as age, gender, associated comorbidities, and obesity. There are no studies available on the relationship between the cause of HF and BNP levels.

In this study, we sought to verify whether BNP levels can identify a poorer prognosis among patients with advanced HF, and whether BNP is an independent prognostic factor considering age, gender, cardiac function, renal function, and cause of heart disease.

Methods

A total of 189 patients admitted to a tertiary care hospital in Sao Paulo, all with advanced HF, systolic dysfunction with ejection fraction < 40%, and in functional class III/IV were prospectively studied. These patients came from the InCor emergency department and were transferred when they could not be compensated after the first measures taken in the emergency department, or when they required inotropic support for compensation. Selection criteria for hospitalization were severe cases with important clinical manifestations.

All patients underwent clinical and laboratory evaluation, including complete blood count and determination of urea, creatinine, BNP, sodium and potassium levels.

Plasma concentration of B-type natriuretic peptide (BNP) was obtained by two-site sandwich immunoassay using direct chemiluminescent technology which uses constant amounts of two monoclonal antibodies. The kit and automated equipment used were ADVIA Centaur^® (Siemens Medical Solutions Diagnostic, Los Angeles, CA, USA). Results are expressed as pg/mL.

As regards the cause of heart disease, the patients were divided into three groups: chagasic, ischemic and non-ischemic heart disease. The diagnosis of chagasic heart disease was confirmed by the presence of positive serologic tests; ischemic heart disease was confirmed by a history of infarction, angina or by coronary cineangiography. In the absence of these characteristics, the patient was considered as having a non-ischemic heart disease.

The patients were followed-up after admission as regards mortality during hospitalization and for one year after discharge. To date, they are still being followed up.

For analysis purposes, we compared the variables of patients who died in-hospital with those of who did not; of patients who died within the first year of follow-up with those patients who did not; and of chagasic with those of non-chagasic patients.

The ROC curve identified the BNP value which best predicted events in patients; the clinical characteristics of patients with values above or below that level were compared.

In the statistical analysis, continuous variables were expressed as mean ± standard deviation, and categorical variables as frequencies and percentages. Patients' characteristics were compared in relation to mortality at the end of the follow-up period. Continuous variables were analyzed using the Mann-Whitney U test, and categorical variables, using the chi-square test or Fisher's exact test. Predictors of mortality were determined by univariate and multivariate analyses, using the Cox proportional hazards method. Based on the follow-up data, the survival curve was constructed using the Kaplan-Meier method. The p values reported are two-tailed, and the significance level was set at < 0.05.

Results

Table 1 shows the main characteristics of the study population; the mean age was 58.8 years, most were males (57.7%), with a mean LVEF of 0.26, and mean BNP level of 1,591.6 pg/mL; 26.5% of patients were chagasic, 25.9% had ischemic heart disease and 47.6% had non-ischemic heart disease. Throughout the study, 30 (15.9%) patients died in hospitalization and 98 (51.9%) within the first year of follow-up.

No significant differences were observed in the clinical and laboratory variables studied among patients who died or not in hospital.

Patients who died in hospital more frequently required vasoactive drugs (80.0% versus 57.2%; p = 0.026), which characterizes them as a group of more severely ill patients.

Patients who died within the first year of follow-up were older, had higher BNP levels (1,861.9 versus 1,408.1 pg/dL; p = 0.044), and higher urea levels (94.4 versus 74.0 mg/dL; p = 0.001). Mortality was higher among chagasic patients and lower among non-ischemic patients (Table 2).

When data from chagasic patients were compared with those of non-chagasic patients, we observed that a higher percentage of chagasic patients required vasoactive drugs to compensate; and that ejection fraction was lower (26.6% versus 27.3%, p = 0.019), and BNP levels were higher (1,985.0 versus 1,452.9 pg/mL; p = 0.001) among chagasic patients. These patients had a worse outcome in the first year of follow-up (mortality of 56% versus 35.3%; p = 0.010); however, in-hospital mortality was not different among chagasic and non-chagasic patients (Table 3).

According to the ROC curve, the BNP level of 1,400 pg / mL was the best predictor of events; high BNP levels were associated with lower LVEF (0.23 versus 0.28; p = 0.002) and with a more severe degree of renal dysfunction (mean urea of 92 versus 74.5 mg/dL; p = 0.002) (Table 4).

Gender and age did not influence BNP levels.

BNP levels > 1,400 pg/mL were also associated with a higher probability of dying in hospital and during follow-up, and were more common among chagasic patients (Table 4).

In the multivariate analysis (Table 5), chagasic heart disease, BNP levels >1,400 pg/dL, and age > 65 years were independent predictors of increased death risk in one-year follow-up in patients hospitalized for decompensated HF.

Figure 1 shows the ROC curve with the identification of the best BNP value to predict events.

Figure 2 shows the survival curves using the Kaplan-Meier method in the first year of follow-up; we can observe that chagasic patients had a poorer outcome than those with heart diseases of other causes. Patients with non-ischemic heart diseases had the best outcome.

Figure 3 shows Kaplan-Meier survival curves in the first year of follow-up for patients with BNP values above or below 1,400 pg/mL; those with higher levels had a poorer outcome than those with lower levels.

Comments

Data show that BNP values help in the prognostic stratification of patients with decompensated advanced HF. Patients with BNP levels >1,400 pg/mL during hospitalization had higher mortality rates either in hospital or within the first year of follow-up. Among the variables studied, BNP level was the best predictor of events. High BNP levels were associated with the need for treatment with inotropic drugs, worse ejection fraction and poorer renal function.

Chagasic patients had higher BNP levels, a poorer outcome, and higher mortality than non-chagasic patients.

The outcome of patients with decompensated HF depends on innumerable clinical variables such as the form of presentation, patient's characteristics, severity of disease, and the treatment the patient had been receiving and will receive during and after cardiac decompensation^1,7-9. Patients with cardiogenic shock, renal failure, Chagas disease, severe myocardial impairment, and those who had been poorly advised comprise the group with a worse outcome; these characteristics are common in the population admitted to our hospital^1,2. More severe cardiac impairment is a possible reason for the relatively high mortality observed among our study population¹.

Together with clinical markers, BNP levels have proven an important non-subjective tool in the identification of more severely ill patients^4,5. BNP levels increase when the patient decompensates, due to ventricular distension; the higher the levels the higher the ventricular distension and, therefore, the more significant the clinical manifestation and severity of decompensation³. Several studies have shown that high BNP levels are able to identify patients with a worse prognosis^3-6. Our study corroborates these findings. This study differs from most studies published because it analyses a population with extremely advanced HF comprised mostly of patients who required vasoactive drugs to compensate and who also presented with renal dysfunction, which is another important prognostic marker in decompensated HF.

High BNP levels are one more finding that permits the characterization of this population as with having extremely advanced HF, because the levels found are much higher than those described in studies with BNP determination in general. We found mean values of 1,500 pg/mL. In the pioneering Maisel et al's study³, the mean BNP value among those diagnosed with HF was 675 pg/mL. In the stratification according to the NYHA functional class III or IV, the mean value described was 900 pg/mL, a value much lower than those found in our study population. In the Val-HeFT study on more than 4,300 patients with chronic HF, the mean BNP values were 97 pg/mL; in patients in functional class III/IV, it was 244 pg/mL¹⁰. In the ADHERE registry, the mean BNP value in the 48,629 patients hospitalized for decompensated HF in the USA was 840 pg/mL¹¹; similar to our findings, higher BNP levels were associated with a higher mortality rate¹¹.

Patients with high BNP levels had more compromised ejection fraction, thus showing the relationship between these higher values and more severe cardiac impairment. Urea levels were also higher, which is usually associated with more severe cardiac involvement and cardiac decompensation, thus identifying patients with a poorer prognosis^1,2. Undoubtedly, more severe impairment of the renal function is one of the factors that may contribute to higher BNP levels because the renal function is frequently associated with more congestion and, therefore, with more ventricular wall stretching and higher release of the peptide¹².

Regardless of the pathophysiology, high BNP levels were important prognostic markers in this population with advanced HF, and were the best predictor of events among the variables studied. Our study found a correlation between BNP values above 1,400 pg/mL and patients who will require a more careful management, so that it is fundamental to optimize treatment in an attempt to modify the natural history of the disease^1,7-9.

This study proves one more time that chagasic patients have a poorer outcome, with a 1.87-times higher death risk than non-chagasic patients^13,14 (Figure 2). The worse outcome of chagasic individuals probably results from more severe cardiac and systemic involvement, findings that are common in this disease¹⁴. In the group studied, we could observe that, despite being younger, chagasic patients more frequently required vasoactive drugs to compensate and had lower ejection fraction, thus characterizing that chagasic individuals show more severe cardiac involvement and a worse clinical status and, consequently, showed more difficulty to respond to the usual treatment without the combination of vasoactive drugs; these findings are related to a poorer prognosis. Given its temporal profile, Chagas disease begins many years prior to the cardiac decompensation and the cardiac involvement progresses slowly, thus permitting the heart and body as a whole to optimize all the compensatory mechanisms, which keeps the patients asymptomatic for years. However, when the patients decompensate, they usually are clinically more refractory to treatment because all their mechanisms are already optimized and no longer able to keep them compensated. In agreement with the greater severity of disease and worse outcome of the population of chagasic patients in this study, their BNP levels were higher than those of non-chagasic patients.

In advanced HF, higher BNP levels identify patients who will potentially have a poorer outcome. Patients hospitalized with BNP values above 1,400 pg/mL comprise a group of very severely ill individuals who have a two-fold higher chance of in-hospital death, and a 1.56-times higher chance of dying within the first year of follow-up in comparison to those with lower BNP levels. BNP level was an excellent predictor of prognosis, with the advantage of not being based on subjective data, in addition to being easily determined. When values >1,400 pg/mL are found, the possibility of optimizing treatment more intensively should be considered, since these patients are those with a higher potential for a poor outcome, and only a well-planned treatment may modify this natural history.

Author contributions

Conception and design of the research: Pereira-Barretto AC, Ramires JAF; Acquisition of data: Pereira-Barretto AC, Cardoso JN, Ochiai ME, Lima MV, Curiati MC, Scipioni AR; Analysis and interpretation of the data: Pereira-Barretto AC, Del Carlo CH, Cardoso JN, Ochiai ME, Curiati MC; Statistical analysis: Del Carlo CH; Writing of the manuscript: Pereira-Barretto AC; Critical revision of the manuscript for intellectual content: Pereira-Barretto AC, Del Carlo CH, Cardoso JN, Ochiai ME, Lima MV, Curiati MC, Ramires JAF.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any post-graduation program.

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Role of BNP levels on the prognosis of decompensated advanced heart failure

Antônio Carlos Pereira-Barretto; Carlos Henrique Del Carlo; Juliano Novaes Cardoso; Marcelo Eid Ochiai; Marcelo Villaça Lima; Milena Cardoso Curiati; Airton Roberto Scipioni; José Antônio Franchini Ramires

Publication Dates

• Publication in this collection
  16 Apr 2013
• Date of issue
  Mar 2013

History

• Received
  07 Mar 2012
• Accepted
  24 Oct 2012
• Reviewed
  14 Mar 2012