Renal Dysfunction and Accuracy of N-Terminal Pro-B-Type Natriuretic Peptide in Predicting Mortality for Hospitalized Patients With Heart Failure

Transcription

1 Circulation Journal Official Journal of the Japanese Circulation Society Advance Publication by-j-stage Renal Dysfunction and Accuracy of N-Terminal Pro-B-Type Natriuretic Peptide in Predicting Mortality for Hospitalized Patients With Heart Failure Domenico Scrutinio, MD; Filippo Mastropasqua, MD; Pietro Guida, BSc; Enrico Ammirati, MD; Vitoantonio Ricci, MD; Rosa Raimondo, MD; Maria Frigerio, MD; Rocco Lagioia, MD; Fabrizio Oliva, MD Background: Renal dysfunction may confound the clinical interpretation of N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentration. This study investigated whether renal dysfunction influences the prognostic accuracy of NT-proBNP in acute decompensated heart failure (ADHF). Methods and Results: We studied 908 ADHF patients. The primary outcome was 12-month mortality. Interaction between estimated glomerular filtration rate (egfr) and NT-proBNP in predicting mortality was tested with the likelihood ratio test. The patients were classified into 3 egfr strata: 60, 30 59, and <30 ml min m 2. Cox models were used to calculate the adjusted hazard ratios (HR) for NT-proBNP, modeled as a dichotomous or categorized variable, within each level of egfr. NT-proBNP was categorized using optimal cut-offs defined in ROC analysis for each egfr level. A total of 234 patients (25.8%) died. Testing for interaction was not significant (χ2 =0.29; P=0.5928). The adjusted HR for NT-proBNP >5,180 pg/ml was 2.09 (P<0.001) in the highest, 1.7 (P<0.001) in the intermediate, and 3.33 (P=0.010) in the lowest egfr level. The adjusted HR for NT-proBNP above the optimal cutoffs defined on ROC analysis were 1.5 (P=0.239), 2.2 (P<0.001), and 3.24 (P=0.002), respectively. The models incorporating NT-proBNP as a dichotomous or categorized variable had equivalent C-statistics. Conclusions: There was no evidence of interaction between egfr and NT-proBNP in predicting mortality. The NT-proBNP cut-off of 5,180 ng/l provided independent prognostic information, irrespective of the level of residual renal function. Key Words: Acute decompensated heart failure; Mortality; N-terminal pro-b-type natriuretic peptide; Prognosis; Renal function Natriuretic peptides (NP) are valuable risk markers in a variety of clinical settings, including elevated risk factors, heart failure (HF), acute coronary syndromes, stable coronary artery disease, intensive care medicine, pulmonary embolism, and cardiac and vascular surgery. 1 7 In the setting of HF, NP testing has been widely adopted in order to improve diagnostic accuracy in dyspneic patients presenting to an emergency department; quantify the severity of illness; assess prognosis; and monitor disease progression, even though it is still under active investigation. 8 NP testing is recommended in current disease-specific guidelines. Given that several factors may influence NP concentration, 2 potentially complicating their clinical interpretation in HF, 2,5,9,10 studies on the influence of these factors on the diagnostic and prognostic accuracy of NP have been conducted. In the Tsutamoto et al study, age, gender, body mass index (BMI), and atrial fibrillation were not independent predictors of brain natriuretic peptide (BNP) level when left ventricular ejection fraction (LVEF) and renal function were concomitantly evaluated. 11 Other studies provided evidence that NP remain prognostic independently of BMI and LVEF. 9,12,13 Renal dysfunction is highly prevalent in acute HF and strongly impacts on prognosis In patients with impaired renal function, NP concentration is markedly raised irrespective of whether HF is present or not, 17,18 suggesting that the N-terminal pro-b-type natriuretic peptide (NT-proBNP) prognostic Received April 7, 2014; revised manuscript received June 11, 2014; accepted June 15, 2014; released online August 26, 2014 Time for primary review: 22 days Division of Cardiology and Cardiac Rehabilitation, S. Maugeri Foundation, IRCCS, Institute of Cassano Murge, Bari (D.S., F.M., P.G., V.R., R.L.); Cardiothoracic and Vascular Department, Niguarda Cà Granda Hospital, Milan (E.A., M.F., F.O.); San Raffaele Scientific Institute and University, Milan (E.A.); and Division of Cardiology and Cardiac Rehabilitation, S. Maugeri Foundation, IRCCS, Institute of Tradate, Varese (R.R.), Italy Mailing address: Domenico Scrutinio, MD, Fondazione S. Maugeri, IRCCS, Istituto di Cassano Murge, Cassano Murge (Bari), Italy. domenico.scrutinio@fsm.it ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 SCRUTINIO D et al. Table 1. Baseline Characteristics vs. egfr All (n=908) >60 (n=409 [45%]) egfr (ml min m 2 ) (n=399 [44%]) <30 (n=100 [11%]) P-value Male Age (years) 66±14 60±15 70±11 72±10 <0.001 BMI (kg/m 2 ) 27±6 27±6 27±6 27± Hypertension <0.001 Diabetes <0.001 COPD Previous CVE Cancer Previous CABG/PTCA <0.001 Chronic liver disease Known dysthyroidism Ischemic etiology <0.001 NYHA IV at admission <0.001 Atrial fibrillation ICD SBP (mmhg) 111±19 110±19 112±18 111± DBP (mmhg) 70±9 70±10 69±9 69± I.v. inotropes <0.001 I.v. diuretics SCr (mg/dl) 1.46± ± ± ±0.95 <0.001 egfr (ml min m 2 ) 58±24 79±17 46±9 22±6 <0.001 NT-proBNP (ng/l), median (IQR) 3,401 2,207 3,948 8,814 <0.001 (1,343 7,922) (997 5,061) (1,668 8,212) (4,999 21,403) Serum sodium (mmol/l) 139± ± ± ± Serum potassium (mmol/l) 4.3± ± ± ±0.6 <0.001 Hb (g/dl) 12.6± ± ± ±1.7 <0.001 LVEF (%) 29±11 29±11 30±11 28± LVEF < (83.3) 343 (83.9) 325 (81.5) 88 (88) LVEF < (57.2) 248 (60.6) 210 (52.6) 61 (61) MR moderate or severe TR moderate or severe <0.001 Data given as mean ± SD, %, n (%) or median (IQR). BMI, body mass index; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; CVE, cerebrovascular event; DBP, diastolic blood pressure; egfr, estimated glomerular filtration rate; Hb, hemoglobin; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; NT-proBNP, N-terminal pro-b-type natriuretic peptide; NYHA, New York Heart Association; PTCA percutaneous coronary angioplasty; SCr, serum creatinine; SBP, systolic blood pressure; TR, tricuspid regurgitation. cut-off may need to be adapted to the level of residual renal function to maximize prognostic accuracy in HF. 19,20 In the most recent Guidelines for the Management of Heart Failure, 21 measurement of NP is recommended for establishing prognosis or disease severity in acutely decompensated heart failure. Clinicians, however, are still advised to be aware that impaired renal function is associated with elevated plasma levels of both BNP and NT-proBNP. 21 The question of whether the NT-proBNP cut-off(s) needs to be adapted to the level of renal function to maximize prognostic accuracy has been incompletely addressed. In the present study, we investigated the effect of renal function on the prognostic accuracy of NT-proBNP in hospitalized patients with acute decompensated HF (ADHF). Methods Nine hundred and twenty-nine patients hospitalized at the Cardiology Division of S. Maugeri Foundation (Bari, Italy), the heart failure unit of the Cardiovascular Department, Niguarda Cà Granda Hospital (Milan, Italy), and the Cardiology Division of S. Maugeri Foundation (Tradate, Varese, Italy) with worsening of chronic, established HF from January 2006 to December 2012 were retrospectively identified using a computer-generated list obtained from the administrative databases and by reviewing electronic and paper medical records. Patients with acute coronary syndrome or angina pectoris, hypertrophic cardiomyopathy, congenital heart disease, valvular heart disease, isolated right ventricular HF, or recent cardiac surgical or percutaneous procedures were excluded. 22 Clinical and laboratory data were collected at admission. LVEF was assessed on 2-D echocardiography. 22 The primary outcome was 12-month all-cause mortality. Death was ascertained by linking with the regional Health Information Systems or by telephone follow-up. The study was approved by the local Institutional Review Board.

3 Renal Dysfunction and NT-ProBNP in HF Figure 1. Median N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentration vs. estimated glomerular filtration rate (egfr). Boxes, interquartile range; vertical lines, 5th and 95th percentiles. Statistical Analysis Data are reported as mean ± SD for continuous variables or number (percentage) for categorical variables. Baseline data were 99.5% complete. Missing data included BMI (6.6%), total cholesterol (5.2%), and diastolic blood pressure at admission (1.8%). Baseline variables were compared using analysis of variance or chi-squared test. Multivariate linear regression analysis was used to confirm the independent association of logtransformed NT-proBNP concentration with estimated glomerular filtration rate (egfr). To assess whether egfr and NT-proBNP were independently associated with risk, a predictive model was developed using univariate and multivariate Cox proportional hazards regression with 1-year mortality as the dependent variable. Baseline characteristics associated with mortality on univariate analysis with P 0.10 were retained for possible inclusion in the final model. We examined the strength and shape of the relationships of continuous variables with the log odds of the primary outcome including non-linear terms and using cubic spline plots. If the response appeared nonlinear, appropriate transformations were applied. The following variables were examined: age (per 10-unit increase); gender; BMI; diabetes, chronic obstructive pulmonary disease (COPD), previous cerebrovascular events, previous coronary artery bypass grafting/percutaneous coronary angioplasty, chronic liver disease, known dysthyroidism, ischemic etiology, atrial fibrillation, New York Heart Association (NYHA) class IV symptoms, implanted cardioverter defibrillator, use of i.v. diuretics or inotropes, systolic blood pressure (SBP; per 10-unit increase), log-transformed egfr, log-transformed NT-proBNP concentration, serum sodium, serum potassium, hemoglobin, LVEF (per 5-unit increase), and moderate-tosevere mitral or tricuspid regurgitation (TR). The patients who underwent heart transplantation (HT) or ventricular assist device (VAD) implantation during follow-up were censored at the time of the event in survival analysis. The distribution of NT-proBNP in non-survivors and survivors within each level of egfr was compared using the 2-sample Kolmogorov- Smirnov test for equality of distribution functions. Statistical significance of the interaction between egfr and NT-proBNP in predicting mortality was tested using the likelihood ratio test by including the 2 variables and their cross-product term in the same multivariate model. To further investigate the effect of renal function on the association of NT-proBNP concentration with time to death, first, we stratified the patients according to egfr into 3 clinical strata: <30 ml min m 2 ; ml min m 2 ; or 60 ml min m We then calculated the hazard ratios (HR) with 95% confidence intervals (95% CI) for NTproBNP concentration, modeled as a dichotomous variable or categorized on the basis of level of renal function, within each egfr level using univariate and multivariate Cox proportional hazards models. To dichotomize NT-proBNP, we used a prespecified cut-off of 5,180 ng/l, the prognostic value of which has been identified and confirmed in previous studies. 22,24 To categorize NT-proBNP concentration according to the level of renal function, receiver operating characteristic (ROC) analysis was performed to identify the optimal cut-off (value with the highest sum of sensitivity and specificity 25 ) within each level of egfr. To compare mortality rates between patient subgroups with NT-proBNP concentration above or below the cut-off of 5,180 ng/l within each level of egfr, HT- and VAD-free survival curves were developed using Cox proportional hazards models. Finally, we substituted logtransformed NT-proBNP with NT-proBNP modeled as a dichotomous (model 1) or categorized variable (model 2) in the multivariate model and re-ran the analysis. The 2 models were compared using measures of global fit and discrimination. We calculated the Akaike information criterion (AIC) and the Bayesian information criterion (BIC), which are tools for model selection; the explained variation (R 2 ), which measures the proportion of the variation in the outcome accounted for through the prognostic index ; 26 and the Harrell C statistic, which is a measure of discrimination. As a sensitivity analysis, we also calculated HR for NT-proBNP cut-offs with 90% sensitivity within each level of egfr. Finally, we also investigated the relation between mortality and in-hospital changes in NT-proBNP and serum creatinine (SCr) concentration in 346 patients with available measurements at admission and discharge (within 48 h before discharge). According to previously published criteria, SCr change was dichotomized at a threshold of 0.3-mg/dl increase and NT-proBNP change at a threshold of >30% decrease; with respect to decrease >30%, both a decrease <30% or an increase portend significantly poorer survival. 27,30 Thus, 4 pa-

4 SCRUTINIO D et al. Figure 2. Receiver operating characteristic curves for N-terminal pro-b-type natriuretic peptide cutoff. AUC, area under the curve; CI, confidence interval; egfr, estimated glomerular filtration rate. Survival and Change in NT-ProBNP and SCr Compared to the patients without available NT-proBNP and SCr measurements at discharge, those with available data had higher NT-proBNP at admission (P=0.003) and more frequenttient subgroups could be distinguished: group 1, NT-proBNP decrease >30% and no SCr rise 0.3 mg/dl; group 2, no NTproBNP decrease >30% and no SCR rise 0.3 mg/dl; group 3, NT-proBNP decrease >30% and SCr rise 0.3 mg/dl; group 4, no NT-proBNP decrease >30% and SCR rise 0.3 mg/dl. Survival curves were developed using multivariate Cox models. Adjusted HR with 95% CI were calculated; the group at lowest risk served as the reference group. Analysis was conducted using Stata 12 (StataCorp, College Station, TX, USA). Results Of the 929 patients, 21 (2.3%) were lost to follow-up, leaving 908 patients available for analysis. Four hundred and nine patients (45%) had egfr 60 ml min m 2 ; 399 (44%) in the range ml min m 2 ; and 100 (11%), <30 ml min m 2. Baseline characteristics across egfr strata are reported in Table 1. Median NT-proBNP was 4-fold higher among the patients with egfr <30 ml min m 2 than among those with egfr 60 ml min m 2. Two hundred and thirty-four patients (25.8%) died and 89 (9.8%) underwent HT or VAD implantation within 1 year. Fifty-three patients (13%) in the highest egfr level died, 126 (31.6%) in the intermediate level, and 55 (55%) in the lowest level. On multivariate regression analysis, egfr was inversely correlated with log-transformed NT-proBNP (adjusted β coefficient = 0.81; P<0.001). Median NT-proBNP across egfr strata for patients who survived or died are shown in Figure 1. The median NTproBNP concentration was higher in the patients who died than in the survivors across all egfr strata. The difference in cumulative distribution functions of NT-proBNP between non-survivors and survivors, as assessed with the 2-sample Kolmogorov-Smirnov test, was highly significant in each level of egfr (P<0.001 for all 3 strata). The D statistic was 0.31 for egfr 60 ml min m 2 ; 0.35 for egfr ml min m 2 ; and 0.49 for egfr <30 ml min m 2. Multivariate predictors of 1-year mortality were age (HR, 1.22; 95% CI: ; P=0.003), COPD (HR, 1.42; 95% CI: ; P=0.015), NYHA class IV (HR, 1.71; 95% CI: ; P<0.001), SBP (HR, 0.9; 95% CI: ; P=0.013), log-transformed egfr (HR, 0.67; 95% CI: ; P=0.005) and NT-proBNP (HR, 1.52; 95% CI: ; P<0.001), serum sodium (HR, 0.96; 95% CI: ; P=0.001), hemoglobin (HR, 0.85; 95% CI: ; P<0.001), LVEF (HR, 0.88; 95% CI: ; P=0.005), and moderate-severe TR (HR, 1.47; 95% CI: ; P=0.005). The likelihood ratio test comparing the model including log-transformed egfr and log-transformed NT-proBNP to the model including their cross-product term yielded χ2 =0.29 (P=0.5928), indicating a lack of statistically significant interaction. The inclusion of the interaction term in the model did not produce any change in the predictive power. The C-statistic was for both models. Figure 2 shows ROC curves for cut-offs selected on ROC analysis. The unadjusted and adjusted HR for the NT-proBNP cut-off of 5,180 ng/l and the optimal cut-offs selected according to the level of renal function across egfr strata are reported in Table 2. Table 2 also shows that renal dysfunction was associated with an increased adjusted risk for 12-month mortality regardless of whether NT-proBNP concentration was below or above the cut-off of 5,180 ng/l. Among the patients with NT-proBNP <5,180ng/L, 12-month adjusted mortality was 10.1% (95% CI: ), 21.1% (95% CI: ), and 22.1% (95% CI: ) in those with egfr 60, 30 59, and <30 ml min m 2, respectively. Among the patients with NT-proBNP >5,180 ng/l, the corresponding mortalities were 28.6% (95% CI: ), 48.9% (95% CI: ), and 68.5% (95% CI: ). Figure 3 shows HT- and VAD-free adjusted survival curves. Measures of model fit and discrimination for the model with NT-proBNP concentrations modeled as a dichotomous (model 1) or categorized variable (model 2) are reported in Table 3. The 2 models had comparable measures of global fit and discrimination The HR for death associated with NT-proBNP cut-offs with 90% sensitivity within each level of egfr was not significant.

5 Renal Dysfunction and NT-ProBNP in HF Table 2. HR for 1-Year Mortality vs. egfr NT-proBNP (ng/l) n 12-month mortality, % (95% CI) Dichotomous cut-off Entire cohort 5, ( ) >5, ( ) egfr (ml min m 2 ) 60 5, ( ) >5, ( ) , ( ) >5, ( ) <30 5, ( ) >5, ( ) Categorized cut-offs Entire cohort ( ) > ( ) egfr (ml min m 2 ) 60 2, ( ) >2, ( ) , ( ) >3, ( ) <30 8, ( ) >8, ( ) CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1. Univariate analysis Multivariate analysis HR (95% CI) P-value HR (95% CI) P-value 4.09 ( ) < ( ) < ( ) < ( ) ( ) < ( ) ( ) < ( ) ( ) < ( ) < ( ) < ( ) ( ) < ( ) < ( ) < ( ) Figure 3. Heart transplantation (HT)- and ventricular assist device (VAD)-free survival curves stratified by estimated glomerular filtration rate (egfr; ml min m 2 ) and N-terminal pro-b-type natriuretic peptide (NT-proBNP; ng/l). justed HT- and VAD-free Kaplan-Meier survival curves according to changes in NT-proBNP and SCr from admission to discharge. The HR with 95% CI adjusted for significant coly had NYHA class IV symptoms (P<0.0001) and severe left ventricular (LV) dysfunction (LVEF <0.30; P=0.003) and required i.v. diuretic treatment (P<0.0001). Figure 4 shows ad-

6 SCRUTINIO D et al. Table 3. Measures of Global Fit and Discrimination Model 1 Model 2 R 2 (95% CI) ( ) ( ) BIC 2, , AIC 2, , C-statistic (95% CI) ( ) ( ) AIC, Akaike information criterion; BIC, Bayesian information criterion. Other abbreviation as in Table 2. variates, including NT-proBNP and SCr at admission, are reported in Table 4. Discussion We investigated the interaction between renal function and NT-proBNP in predicting mortality for patients hospitalized with ADHF. The major findings are: (1) there was no statistically significant interaction between egfr and NT-proBNP in relation to 1-year mortality risk prediction; (2) irrespective of the level of renal function, the NT-proBNP cut-off of 5,180 ng/l retained a significant prognostic value; and (3) use of a triple cut-off based on egfr did not improve the performance of the predictive model. As expected, we found an inverse correlation between egfr and NT-proBNP. Median NT-proBNP increased with decreasing egfr both in non-survivors and survivors, with a steep increase in the lowest egfr level (<30 ml min m 2 ). Of interest, the trend of the differences in cumulative distribution of NT-proBNP between non-survivors and survivors across egfr strata suggests a decreasing overlap of NT-proBNP with advancing renal dysfunction. No statistically significant interaction, however, between egfr and NT-proBNP and 1-year mortality, was seen. After adjusting for the covariates independently associated with mortality risk, the NT-proBNP cut-off of 5,180 ng/l was associated with a significantly increased hazard for death across all 3 strata of renal function. Conversely, when multiple cut-offs selected on ROC analysis according to level of renal function were applied, that for the subgroup with preserved renal function ( 60 ml min m 2 ) was not independently associated with increased mortality. It should, however, be considered that the lower event rate in this subgroup may have biased the estimate for the optimal cut-off. The hazard for death associated with elevated NT-proBNP was greater in the lowest (egfr <30 ml min m 2 ) than in the intermediate or highest egfr level. In the lowest egfr level, the HR for death was >3, meaning that the patients with severely impaired renal function and elevated NT-proBNP concentration had a >3-fold likelihood of dying within 1 year compared with their counterparts with NT-proBNP below the cut-off. Visual inspection of the survival curves also shows that the difference in mortality between patients with NT-proBNP above or below the cut-off progressively increased with declining renal function. It is relevant to note that survival curves began to diverge very early, especially in the subgroup with severe renal dysfunction, and continued to separate throughout the follow-up. Moreover, it should be noted that the area under the curve for optimal cut-offs selected on ROC analysis progressively increased across decreasing egfr (Figure 2). Collectively, these data indicate that the discriminative value of NT-proBNP in predicting death improves with declining renal function. Although changes in AIC and BIC suggest that the predictive model incorporating NT-proBNP cut-offs adapted to the level of residual renal function performed better than the same model including the single cut-off of 5,180 ng/l, the hazard of death conferred by elevated NT-proBNP in the entire cohort, the explained variation, and the discriminative ability, which remains the primary criterion to assess the performance of a predictive model, 31 were virtually equivalent for the 2 models. The present findings strongly suggest that higher NT-proB- NP concentration in hospitalized patients with ADHF and markedly decreased egfr do not merely result from decreased renal filtration or impaired renal clearance but are mostly associated with disease severity and prognosis. This is in keeping with the mechanistic study by van Kimmenade et al indicating that, in patients with egfr <60 ml min m 2, NT-proBNP concentration may be more determined by cardiac production than renal clearance, 32 and with other studies assessing the prognostic value of NP in dialysis patients. 20 The finding that the triple cut-point strategy 24 based on egfr level did not improve the predictive accuracy of the multivariate model supports the use of a single NT-proBNP cut-off for risk prediction. In addition, the use of a prespecified cut-off may allow reduction of the potential bias in selecting optimal cut-off value(s) with a data-driven approach. 33 Finally, we also examined the relationship between mortality and changes in NT-proBNP and SCr concentration from admission to discharge. It is generally accepted that worsening renal function (WRF), defined as an increase in SCr 0.3 mg/dl during hospitalization, negatively impacts on survival in ADHF. 34 The present data suggest that the impact of WRF on mortality risk is influenced by the pattern of change in NTproBNP concentration. Indeed, WRF was not related to increased mortality risk unless associated with persistently elevated or increased NT-proBNP. Among the patients who had a decrease in NT-proBNP >30% during hospitalization, those with or without WRF had similar survival. These findings, obtained in a subset of 346 patients with available data at discharge, however, need to be confirmed by larger studies. Previous Studies The prognostic accuracy of NT-proBNP in ADHF patients with concomitant renal dysfunction has been addressed in a few studies. defilippi et al studied 831 dyspneic patients presenting to emergency departments, of whom 437 (53%) had decompensated HF. 17 Among HF patients with renal dysfunction, progressively higher NT-proBNP concentration remained predictive of increased 1-year mortality. van Kimmenade et al analyzed the association of NT-proBNP and renal function with mortality in 720 patients with acute HF enrolled in the International Collaborative on NT-proBNP (ICON) study. 35 They found that the combined use of egfr and NT-proBNP allows identification of patients at highest risk of mortality. In that study, however, the length of follow-up was limited to 60 days and only 84 fatal events were recorded. Thus, confirmatory data are warranted. In addition, the question of whether the use of NT-proBNP cut-offs adapted to level of renal function allows maximization of prognostic accuracy has been incompletely addressed. The present findings are in line with the results obtained by defilippi et al and van Kimmenade et al. 17,35 NT-proBNP was independently associated with an increased mortality risk in patients with renal dysfunction, especially in those with severe renal dysfunction. In addition, we showed that, although median NT-proBNP was 4-fold higher among the patients with

7 Renal Dysfunction and NT-ProBNP in HF Figure 4. Adjusted heart transplant- and ventricular assist device-free Kaplan-Meier survival curves according to changes in N- terminal pro-b-type natriuretic peptide and serum creatinine (SCr) from admission to discharge. Table 4. HR and 95% CI for NT-ProBNP and SCr Change Group 1 (reference) Group 2 Group 3 Group 4 NT-proBNP change Decrease >30% No decrease >30% Decrease >30% No decrease >30% SCr change (mg/dl) No SCr rise 0.3 No SCr rise 0.3 SCr rise 0.3 SCr rise 0.3 n Unadjusted HR (95% CI) ( ) 1.13 ( ) 3.62 ( ) P-value < <0.001 Adjusted HR (95% CI) ( ) 0.93 ( ) 2.55 ( ) P-value < Abbreviations as in Tables 1,2. severely impaired renal function than among those with normal renal function, there was no need to adapt NT-proBNP cut-off to the level of residual renal function to maximize prognostic accuracy. Perhaps, the present data may also have implications for patients with end-stage renal disease in whom a prevalence of HF of 31 40% has been reported. 20 Study Limitations This was a retrospective study. Data were derived from a cohort of patients with predominant systolic HF, most of whom had severe LV systolic dysfunction. Given that patients with reduced LVEF may reasonably have higher NT-proBNP concentration than those with preserved LVEF within the same range of renal function, the results may not be generalizable to HF patients with preserved LV systolic function. Women represented only 23.1% of the study sample. This is consistent with the finding that the majority of acute HF patients with LV systolic dysfunction are men. 36 We used all-cause mortality instead of cardiovascular mortality as the primary outcome; this may be another limitation. All-cause death, however, was recognized as a harder end point, relatively unbiased, easily ascertained, and the most valid. 37 Moreover, establishing the cause of death in observational studies can be very difficult and inaccurate, 37 making the outcome of cardiac death susceptible to misclassification bias. 37,38 Finally, it should be considered that, in patients hospitalized with worsening HF and reduced LVEF, cardiovascular death accounts for nearly 90% of all-cause deaths occurring in the months following discharge. 39 Conclusions There was a lack of interaction between renal dysfunction and NT-proBNP in predicting 1-year mortality for patients hospitalized with ADHF. A single NT-proBNP cut-off provided important prognostic information, irrespective of the level of residual renal function. Stratification of NT-proBNP concentration based on clinical renal function level did not result in

8 SCRUTINIO D et al. improved predictive accuracy for 1-year mortality. Disclosures No conflict of interest to be declared. References 1. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004; 350: Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007; 50: Di Angelantonio E, Chowdhury R, Sarwar N, Ray KK, Gobin R, Saleheen D, et al. B-Type natriuretic peptides and cardiovascular risk: Systematic review and meta-analysis of 40 prospective studies. Circulation 2009; 120: Maisel A, Mueller C, Adams K Jr, Anker SD, Aspromonte N, Cleland JG, et al. State of the art: Using natriuretic peptide levels in clinical practice. Eur J Heart Fail 2008; 10: Thygesen K, Mair J, Mueller C, Huber K, Weber M, Plebani M, et al. Recommendations for the use of natriuretic peptides in acute cardiac care: A position statement from the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Eur Heart J 2012; 33: Levy WC. Can B-type natriuretic peptides replace heart failure risk models? Eur J Heart Fail 2008; 10: Pascual-Figal DA, Manzano-Fernández S, Boronat M, Casas T, Garrido IP, Bonaque JC, et al. Soluble ST2, high-sensitivity troponin T- and N-terminal pro-b-type natriuretic peptide: Complementary role for risk stratification in acutely decompensated heart failure. Eur J Heart Fail 2011; 13: Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor heart failure therapy. Clin Chem 2012; 58: van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, et al. B-Type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013; 61: Januzzi JL Jr. Natriuretic peptides, ejection fraction, and prognosis: Parsing the phenotypes of heart failure. J Am Coll Cardiol 2013; 61: Tsutamoto T, Wada A, Sakai H, Ishikawa C, Tanaka T, Hayashi M, et al. Relationship between renal function and plasma brain natriuretic peptide in patients with heart failure. J Am Coll Cardiol 2006; 47: Schou M, Gustafsson F, Kistorp CN, Corell P, Kjaer A, Hildebrandt PR. Effects of body mass index and age on N-terminal pro brain natriuretic peptide are associated with glomerular filtration rate in chronic heart failure patients. Clin Chem 2007; 53: Christenson RH, Azzazy HM, Duh SH, Maynard S, Seliger SL, defilippi CR. Impact of increased body mass index on accuracy of B-type natriuretic peptide (BNP) and N-terminal probnp for diagnosis of decompensated heart failure and prediction of all-cause mortality. Clin Chem 2010; 56: Butlet J, Chirovsky D, Phatak H, McNeill A, Cody R. Renal function, health outcomes, and resource utilization in acute heart failure: A systematic review. Circ Heart Fail 2010; 3: Shirakabe A, Hata N, Kobayashi N, Shinada T, Tomita K, Tsurumi M, et al. Prognostic impact of acute kidney injury in patients with acute decompensated heart failure. Circ J 2013; 77: Sato N, Kajimoto K, Keida T, Mizuno M, Minami Y, Yumino D, et al. Clinical features and outcome in hospitalized heart failure in Japan (from the ATTEND Registry). Circ J 2013; 77: defilippi CR, Seliger SL, Maynard S, Christenson RH. Impact of renal disease on natriuretic peptide testing for diagnosing decompensated heart failure and predicting mortality. Clin Chem 2007; 53: Forfia PR, Watkins SP, Rame JE, Stewart KJ, Shapiro EP. Relationship between B-type natriuretic peptides and pulmonary capillary wedge pressure in the intensive care unit. J Am Coll Cardiol 2005; 45: Palazzuoli A, Masson S, Ronco C, Maisel A. Clinical relevance of biomarkers in heart failure and cardiorenal syndrome: The role of natriuretic peptides and troponin. Heart Fail Rev 2014; 19: Wang AY. Clinical utility of natriuretic peptides in dialysis patients. Semin Dial 2012; 25: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128: e240 e319, doi: /cir.0b013e31829 e Scrutinio D, Ammirati E, Guida P, Passantino A, Raimondo R, Guida V, et al. Clinical utility of N-terminal pro-b-type natriuretic peptide for risk stratification of patients with acute decompensated heart failure: Derivation and validation of the ADHF/NT-proBNP risk score. Int J Cardiol 2013; 168: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1 S Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez- Llanos J, Santalo-Bel M, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: An international pooled analysis of 1256 patients. The International Collaborative of NT-proBNP Study. Eur Heart J 2006; 27: Zou KH, O Malley AJ, Mauri L. Receiver-operating characteristic analysis for evaluating diagnostic tests and predictive models. Circulation 2007; 115: Royston P. Explained variation for survival models. Stata J 2006; 6: Bettencourt P, Azevedo A, Pimenta J, Friões F, Ferreira S, Ferreira A. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 2004; 110: Damman K, Valente MA, Voors AA, O Connor CM, van Veldhuisen DJ, Hillege HL. Renal impairment, worsening renal function, and outcome in patients with heart failure: An updated meta-analysis. Eur Heart J 2014; 35: Givertz MM, Postmus D, Hillege HL, Mansoor GA, Massie BM, Davison BA, et al. Renal function trajectories and clinical outcomes in acute heart failure. Circ Heart Fail 2014; 7: Carrasco-Sánchez FJ, Pérez-Calvo JI, Morales-Rull JL, Galisteo- Almeda L, Páez-Rubio I, Barón-Franco B, et al. Heart failure mortality according to acute variations in N-terminal pro B-type natriuretic peptide and cystatin C levels. J Cardiovasc Med (Hagerstown) 2014; 15: Pencina MJ, D Agostino RB, D Agostino Jr RB, Vasan RS. Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond. Stat Med 2008; 27: van Kimmenade RR, Januzzi JL Jr, Bakker JA, Houben AJ, Rennenberg R, Kroon AA, et al. Renal clearance of B-type natriuretic peptide and amino terminal pro-b-type natriuretic peptide: A mechanistic study in hypertensive subjects. J Am Coll Cardiol 2009; 53: Leeflang MMG, Moons KGM, Reitsma JB, Zwinderman AH. Bias in sensitivity and specificity caused by data-driven selection of optimal cutoff values: Mechanisms, magnitude, and solutions. Clin Chem 2008; 54: Greenberg B. Acute decompensated heart failure: Treatments and challenges. Circ J 2012; 76: van Kimmenade RR, Januzzi JL Jr, Baggish AL, Lainchbury JG, Bayes-Genis A, Richards AM, et al. Amino-terminal pro-brain natriuretic peptide, renal function, and outcomes in acute heart failure: Redefining the cardiorenal interaction? J Am Coll Cardiol 2006; 48: Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53: Hachamovitch R, Di Carli MF. Methods and limitations of assessing new noninvasive tests: Part II: Outcomes-based validation and reliability assessment of noninvasive testing. Circulation 2008; 117: Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: Time for a reassessment? J Am Coll Cardiol 1999; 34: O Connor CM, Miller AB, Blair JEA, Konstam MA, Wedge P, Bahit MC, et al. Causes of death and rehospitalizations in patients hospitalized with worsening heart failure and reduced left ventricular function: Results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program. Am Heart J 2010; 159: