The present prospective observational study was carefully designed to meet the requirements for a prognostic evaluation of biomarkers. Contrary to randomized studies, patients are unselected and included on a consecutive basis which offers a great advantage for risk identification.
In this study we have included admission samples of the two biomarkers BNP and hsCRP, to investigate their impact on prognosis in patients with chest pain and suspected ACS, and we have discriminated between patients with and without a release of TNT.
It has been suggested that the combined assessment of natriuretic peptides and CRP may yield incremental prognostic information in the risk stratification of patients with ACS [2, 3], and their combined use has been shown to improve long-term risk prediction of mortality in patients with stable coronary heart disease (CHD) .
In the stepwise multivariate model applied to the total chest-pain patient material we included the presence and absence of a TnT release and were able to demonstrate a statistical significant prognostic impact of BNP and hsCRP, respectively, on 2 year survival, both for total and cardiac mortality.
In the TnT positive subgroup we found a statistically significant prognostic impact of BNP in the stepwise multivariate Cox regression model on all cause mortality and cardiac mortality, whereas hsCRP was found to be related only to total mortality.
In a univariate discriminant analysis we found that a TnT positive event was correctly classified by BNP or hsCRP in over 60% of cases. The specificity of BNP and hsCRP for predicting all cause mortality of the total population was around 90% for both biomarkers, associated with a sensitivity of 44.5 and 31.9%, respectively.
In the present study, patients in the highest quartile of both BNP and hsCRP were older and a higher proportion had a TnT exceeding 0.01 ng/ml. In the highest quartile of BNP there were also more past smokers and subjects with established CHD and HF, and creatinine was also increased. These differences reflect the increased burden of risk in the upper quartiles of BNP and hsCRP, respectively. Despite some similarities in underlying risk burden, these two predictors are mechanistically different. However, their combination did not strengthen the prognostic utility.
Our results indicate that both BNP and hsCRP are major predictors of outcome in a population in which invasive coronary intervention is less available as compared to wealthier communities, as only 29% of the total population and 38% of the TnT positive population underwent a revascularization procedure during the hospitalization for the index event.
Thirty-one percent of the TnT positive population was classified as STEMIs, and of these patients only 42% were treated with primary PCI. Furthermore, the use of thrombolytic therapy in this region of Argentina is uncommon and was not applied in our patient cohort. The less frequent use of reperfusion treatment in STEMI patients makes this population unique in an epidemiological setting, optimizing an evaluation of prognostic indicators in relation to the natural course of disease.
The results of this observational study is in accordance with previous studies investigating the prognostic impact of BNP  and hsCRP , and also emphasize the importance of several clinical background factors in this respect [23–25]. After adjusting for clinical covariates, the prognostic utility of BNP as well as hsCRP remained statistically significant with respect to total mortality in both the total population and in the TnT positive patients.
It was shown in the mid 90-ies that elevated troponins are associated with a worsened prognosis in ACS patients . Since then, a considerable number of publications have verified the prognostic significance of this biomarker in this patient setting . Its prognostic utility exceeds that of all other biomarkers, including BNP  and hsCRP .
Based on previous studies [14, 15, 22, 28] addressing the prognostic utility of hsCRP, this biomarker has been considered for adoption into risk assessment algorithms [1, 29]. Recently conducted studies show that the predictivity of hsCRP is attenuated when tested in a multivariable model in the general population  and together with natriuretic peptides in patients with known CAD [31–34]. In our study hsCRP seems to be a potential predictor for all cause mortality, also when adjusted for BNP, but does not reflect cardiac mortality in the TnT positive population when introducing BNP into the model.
In contrast to hsCRP, natriuretic peptides integrate specific pathophysiological signals, especially relating to ventricular dysfunction [5, 35] and ischemic burden . The main prognostic impact of BNP was found in the TnT positive patients, suggesting a relation to ischemia.
The measurement of prognostic biomarkers has often been performed in randomized interventional trials several days following the onset of symptoms and hospitalization [8, 10, 29]. In contrast to the majority of previous studies investigating the prognostic impact of various biomarkers, our study had a prospective and observational design, and blood samples were collected directly on admission.
Few studies have examined the predictive value of natriuretic peptides across the spectrum of chest-pain patients with suspected ACS in blood samples obtained directly on admission before introduction of therapy . Therefore, in the present study which is similar to a previous study performed by our group , we do not have to consider the potential confounding factors of late inclusions and recently introduced medical treatment. Similar considerations apply to the measurement of hsCRP.
A major strength of this study is the absence of patients lost to follow-up and there were only four patients with no measurements available for hsCRP. Moreover, our study was performed in an inhomogeneous and unselected chest-pain population with suspected ACS which is representative of the one commonly dealt with in the ED.
Our study suggests that BNP and/or hsCRP in addition to the troponins may be supplementary biomarkers in risk stratification. However, their impact in the clinical prognostic assessment of ACS patients depends on the presence of troponin release. By including patients with borderline troponin levels ≤ 0.05 ng/mL among the TnT negative patients and without adjusting for a positive troponin value, the HR of BNP for cardiac death in Q4 as compared to Q1 in the multivariate Cox regression model was 3.58 (95% CI, 1.02-12.60), p = 0.047, in this extended patient category. The same relation was observed for hsCRP; HR of 2.69 (95% CI, 1.22-5.95), p = 0.015, suggesting that the use of BNP or hsCRP may strengthen the clinical prognostic assessment in this subgroup.
The potential limitations of these data merit consideration. The circulating concentrations of BNP and hsCRP prior to hospitalization remain unknown and our analyses are based on a single baseline determination. Although we did not adjust for LVEF, we did adjust for known CHF and CVD, including previous MI, and other clinical risk factors.