a b s t r a c t

Objectives: Acute heart failure is a leading cause of admission in emergency departments (ED). It is associ- ated with significant in-hospital mortality, suggesting that there is room for improvement of care. Our aims were to investigate clinical patterns, biological characteristics and determinants of 30-day mortality.

Methods: We conducted a single site, retrospective review of adult patients (>=18 years) admitted to ED for AHF over a 12-month period. Data collected included demographics, clinical, biological and outcomes data. Epidemi- ologic data were collected at baseline, and patients were followed up during a 30-day period.

Results: There were a total of 322 patients. Mean age was 83.9 +- 9.1 years, and 47% of the patients were men. Among them, 59 patients (18.3%) died within 30 days of admission to the ED. The following three characteristics were associated with increased mortality: age N 85 years (OR = 1.5[95%CI:0.8-2.7], p = 0.01), creatinine clear- ance b 30 mL/min (OR = 2.6[95%CI:1.4-5], p b 0.001) and Nt-proBNP N 5000 pg/mL (OR = 2.2[95%CI:1.2-4],

p b 0.001). The best Nt-proBNP cut-off value to predict first-day mortality was 9000 pg/mL (area under the curve (AUC) [95%CI] of 0.790 [0.634-0.935], p b 0.001). For 7-day mortality, it was 7900 pg/mL (0.698 [0.578-

0.819], p b 0.001) and for 30-day mortality, 5000 pg/mL (0.667 [0.576-0.758], p b 0.001).

Conclusions: Nt-proBNP level on admission, age and creatinine clearance, are predictive of 30-day mortality in adult patients admitted to ED for AHF.

(C) 2016

1. Introduction

acute heart failure is a leading cause of admission in emergen- cy departments (ED) in Western countries. Its prevalence is estimated at between 1 and 2% of the adult population and is higher than 10% in pa- tients older than 70 years [1-3]. Recommendations for diagnosis and management of AHF were issued by the European Society of Cardiology (ESC) in 2016 [4] and by the American Heart Association (AHA) in 2013 [5] with an update in 2016 [6]. Initial diagnosis is based on clinical history, physical examination and electrocardiogram (ECG). Some abnor- malities on ECG provide information on aetiology and may give indica- tion for therapy. The plasma concentration of Natriuretic peptides (B- type natriuretic peptide [BNP] and N-terminal pro-BNP [Nt-proBNP]) can be used as a complementary diagnostic test. Echocardiography pro- vides crucial information on chamber volumes, ventricular systolic and Diastolic function, valve function and pulmonary hypertension [5-7].

* Corresponding author at: Emergency Department, University Hospital of Poitiers, 2 Rue de la Miletrie, 86000 Poitiers, France.

E-mail address: [email protected] (M. Marchetti).

The information provided by the above-mentioned tests and clinical evaluation allow for initial treatment plan in most patients.

AHF is associated with significant in-hospital mortality and high rates of rehospitalization after discharge [8]. Early identification of pa- tients at high risk of death might help emergency physicians to optimize their prompt management and thus expect an improvement in progno- sis. The aim of this study was to determine the clinical and biological patterns that could successfully predict the short-term prognosis (30- day mortality) of patients with AHF at the time of admission to the ED.

1. Methods
   1. Study design and population

We conducted a single site, retrospective study to assess risk factors associated with 30-day mortality in patients with AHF. We reviewed the clinical course of 322 patients, 18 years or older, admitted to ED with the primary diagnosis of AHF, in a large academic center, between January 1 and December 31, 2014. The outcome in this study was defined as 30- day mortality. Patients surviving and not surviving the 30-day period after discharge were matched with their clinical and biological data.

http://dx.doi.org/10.1016/j.ajem.2016.11.050

0735-6757/(C) 2016

M. Marchetti et al. / American Journal of Emergency Medicine 35 (2017) 444–447 445

Data were anonymized and stored electronically. The study was con- ducted in accordance with the principles of the Declaration of Helsinki. According to French law, institutional review board approval was not requested due to the retrospective design of the study and the use of anonymous data only.

Study protocol

Data collection was performed using patients’ computerized medical records. Final diagnosis at ED discharge was used for inclusion and med- ical records were retrospectively reviewed to ensure that the 2012 ESC Guidelines [1] criteria were met for the diagnosis of AHF. Medical histo- ry, demographics, clinical and biological data were collected with the following software: ResUrgences(R) (Intuitive, Paris, France), Hopital Manager(R) (Softway Medical, Meyreuil, France) and CyberLab(R) (Clini- cal Biology Institute, Brussels, Belgium). All data were recorded at base- line, and patients’ vital status at 30 days was ascertained by consulting hospital registries. In case of death within 30 days from ED admission, the interval (days) between admission and death was also recorded. When patients returned home before the thirtieth day, vital status was ascertained by telephone contact with the patient’s general practi- tioner. No patient was lost during the 30-day follow up. For patients who presented to the ED more than once, only data from their First visit were included in the study. According to ESC Guidelines, patients were classified into six clinical presentations of AHF: acute pulmonary edema, cardiogenic shock, acutely decompensated chronic heart failure (CHF), hypertensive heart failure (HF), isolated right HF and acute cor- onary syndrome (ACS) with HF. Severe renal insufficiency was defined as a creatinine clearance according to Modification of Diet in Renal Dis- ease (MDRD) formula lower than 30 mL/min/1.73m².

Statistical analysis

Data were recorded using Excel(R) software (Microsoft Corporation, Richmond, USA). Statistical analyses were performed using SPSS 21.0 software (IBM Corporation, Armonk, NY, USA). Comparative univariate analyses were performed using the Chi-square test and Fisher’s test for percentage comparisons. Differences in continuous variables were eval- uated by the Student t-test. The log-rank test, odd-ratios (OR) with 95% confidence intervals (CI) and receiver operating characteristic (ROC) analyses were used to determine the prognostic value of clinical and bi- ological patterns on 30-day mortality. All tests were two-tailed and sta- tistical significance was considered for p <= 0.05.

1. Results

Overall, 322 patients with a primary diagnosis of AHF and complete data were analyzed. Their mean age was 83.9 +- 9.1 years and 47% of them were men (Table 1). Sixty percent of the patients were older than 85 years. Evidence of chronic heart failure was reported in 88.8% of cases. The most common co-morbidities were hypertension (74.5%) and atrial fibrillation (54.3%). Acutely decompensated CHF was the most frequent clinical presentation (58.1%). Acute pulmonary edema was present in 14.3%, while hypertensive HF, ACS with HF, isolated right HF and cardiogenic shock was reported respectively in 11.5, 6.2,

5.6 and 4.3% (Table 1). A total of 59 (18.3%) patients died within 30 days of admission to the

ED. Their clinical presentations were acutely decompensated CHF in 44.1% of cases, and acute pulmonary edema, cardiogenic shock and ACS with HF in 16.9, 15.2 and 11.8% of cases, respectively (Table 1). On univariate analysis, clinical pictures associated with 30-day

Table 1

SD : Standard Deviation, COPD : Chronic Obstructive Pulmonary Disease, HF : Heart Failure, MDRD : Modification of diet in renal disease.

446 M. Marchetti et al. / American Journal of Emergency Medicine 35 (2017) 444–447

mortality were cardiogenic shock (OR = 9.3 [95%CI: 3-28.9], p b 0.001) and ACS with HF (OR = 2.6 [95%CI: 1-6.8], p = 0.02) (Table 1). Systolic blood pressure under 90 mm Hg at presentation was associated with higher mortality (OR = 13.6 [95%CI: 3.5-53.0], p b 0.001). By contrast, medical history of coronary heart disease (OR = 0.5 [95%CI: 0.26-1], p = 0.05) and atrial fibrillation (OR = 0.5 [95%CI: 0.3-0.9], p = 0.02) were associated with lower mortality (Table 1).

Predictors for 30-day mortality were age N 85 years (OR = 1.5[95%CI:0.8-2.7], p = 0.01), severe renal insufficiency (OR = 2.6[95%CI:1.4-5], p = 0.001) and Nt-proBNP N 5000 pg/mL (OR =

2.2[95%CI:1.2-4], p b 0.001). The optimal Nt-proBNP cut-off value for predicting 30-day mortality was 5000 pg/mL (Area under the curve (AUC) [95%CI]: 0.667 [0.576-0.758], p b 0.001) (Fig. 1). The cut-off for

predicting first-day and seven-day mortality were 8991 pg/mL (0.790 [0.634-0.935], p b 0.001) and 7900 pg/mL (0.698 [0.578-0.819],

p b 0.001), respectively. Kaplan-Meier survival curves confirm that pa- tients with NT-proBNP levels above 5000 pg/mL had significantly (p = 0.02) higher 30-day mortality than patients with Nt-proBNP levels below this cut-off (Fig. 2).

1. Discussion

Our study showed that age N 85 years, creatinine clearance (MDRD formula) b 30 mL/min and Nt-proBNP level N 5000 pg/mL are three early predictors of 30-day mortality in elderly patients admitted to ED for AHF.

The mean age of our patients was 84 years. This is comparable than in most other recent studies [8-11]. Co-morbidities and clinical presen- tations were similar to those reported in most other studies or registries [5-7,12,13]. These findings are comparable to those observed in large registries of AHF such as the OPTIMIZED-HF registry [14] including N 48,000 patients in the USA and the OFICA study [15], a single-day snapshot among 1868 patients in French hospitals. In these studies, mean age was closed to 80 years, and the majority of patients were over 85 years. Similarly, as in our results, patients with cardiogenic shock represented 4 to 6% of cases, and the EHFS-II study [9] show a 16% acute pulmonary edema rate. Many of our patients had a history of Atrial fibrillation , which may be explained by the increase in the prevalence of AF with age [16]. The majority of our patients had a medical history of chronic heart failure, as in most similar studies [9-15].

In our study, 30-day mortality was 18.3%. It was higher than in sim- ilar studies on short-term mortality (1-day or 7-day) [11-13,15]. Ina prospective study, Golcuk et al. [17] examined 100 patients with AHF at ED admission, with a 30-day mortality of 21%. In two other studies, Aaronson et al. [18] and Krumholz et al. [19] found a lower 30-day mor- tality of 11%. Fabbri et al. [20] found a 30-day and one-year mortality of

10 and 50%, respectively. In our study, clinical presentation of

Fig. 2. Kaplan-Meier survival curves according to initial Nt-proBNP level above or below 5000 pg/mL.

cardiogenic shock and ACS with HF were associated with higher mortal- ity, and systolic blood pressure below 90 mm Hg is an acknowledged criterion for intensive care unit admission [4]. But surprisingly, medical history of AF and coronary heart diseases were associated with a lower rate of death. This may be explained by more extensive follow-up of these patients, with Optimal treatment [14,15].

Several studies reported admission Nt-proBNP cut-off value as a risk stratification tool and prognostic indicator in patients with AHF [21-25]. The 30-day mortality period seemed to be more pertinent from a path- ophysiological point of view, than shorter duration (first day) or longer (1 to 4 years) duration. However, from an emergency physician per- spective, 1-day and 7-day mortality could be considered even more im- portant, as these early endpoints may help driving ED therapy and ICU admission. Cardiologists and intensivists interventions may also impact late mortality, but overall survival is mainly determined by the quality of the initial management [4-6]. With our study design, we could assess the association with mortality of the variables classically described as prognostic predictors. Analysis of the area under the ROC curve suggests that a Nt-proBNP cut-off value of 5000 pg/mL provides prognostic infor- mation regarding 30-day survival in our ED population admitted for AHF. Gegenhuber et al. [26] found an optimal Nt-proBNP cut-off point of 2060 pg/mL for predicting 1-year mortality. In another study, Velibey et al. [27] showed that Nt-proBNP value of 2300 pg/mL is a predictive factor of 4-year mortality. Our study reinforces Nt-proBNP as the stan- dard for AHF Prognostic prediction and helps to better define subgroups

Fig. 1. Receiver operating characteristic curves of Nt-proBNP cut-off values as predictors of 1-day (A), 7-day (B) and 30-day mortality (C).

M. Marchetti et al. / American Journal of Emergency Medicine 35 (2017) 444–447 447

in need of more intensive care [16-27]. Older age (N 85 years) and se- vere renal insufficiency were also associated with 30-day mortality. This correlation has been found in several similar studies [28-32].

These findings suggest that in elderly patients presenting to the ED with AHF, assessment of Nt-proBNP concentrations could also be useful to stratify patients according to their prognosis. We suggest that prompt aggressive treatment should be applied to patients with Nt-proBNP levels above 5000 pg/mL, to reduce in-hospital and short-term mortal- ity. This includes identification of causes leading to AHF and requiring urgent management (acute coronary syndrome, hypertensive emer- gency, acute pulmonary embolism, arrhythmias), search of criteria for hospitalization in ICU, and management of the early phase with oxygen therapy, diuretics, vasodilators (in the absence of symptomatic hypo- tension) or other drugs (digoxin, amiodarone, thrombo-embolism pro- phylaxis) as per ESC and AHA guidelines [4,6].

Some study limitations should be acknowledged. It was a single- center study, with patients potentially not representative of the whole population of patients with AHF. However, the characteristics of our population were similar to those observed in large registries. Despite systematic recruitment with computerized medical records, the analy- sis was retrospective with all its inherent setbacks. Our population was not homogenous with regard to clinical presentation: acutely de- compensated CHF was the most common presentation (58%), while car- diogenic shock, with higher mortality, was reported in only 4%. Biological data were collected at the time of ED admission, and our anal- yses were based on a single baseline determination, thereby precluding any comparison between admission and pre-mortem data values or variations. Moreover, the effects of unmeasured variables such as dura- tion of AHF, socioeconomic factors and obesity cannot be excluded.

1. Conclusion

Nt-proBNP level >= 5000 pg/mL on admission, age and severe renal failure are predictors of all-causes 30-day mortality in elderly patients admitted to ED for AHF. Additional large, prospective and multicenter studies are needed to confirm our findings.

Acknowledgement

The authors would like to thank Mr. Jeffrey Arsham for copy editing the manuscript.

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