Validation of the Grace Risk Score to Predict In-Hospital and 6-Month Post-Discharge Mortality in Patients with Acute Coronary Syndrome

Background: The wide range of clinical presentations of acute coronary syndrome (ACS) makes it indispensible to use tools for risk stratification and for appropriate risks management; thus, the use of prognosis scores is recommended in the immediat clinical decision-making. Objective: To validate the Global Registry of Acute Coronary Events (GRACE) score as a predictor of in-hospital and 6-month post-discharge mortality in a population diagnosed with ACS. Methods: This is a prospective cohort study of consecutive patients diagnosed with ACS between May and December 2018. GRACE scores were calculated, as well as their predictive value for in-hospital and 6-month postdischarge mortality. The validity of the model was assessed by two techniques: discriminative power using the area under the receiver operating characteristic curve (AUC) and goodness-of-fit, using the Hosmer-Lemeshow (HL) test, at the 5% level of significance. Results: A total of 160 patients were included, mean age 64 (±10.9) years; of which 60% were men. The risk model showed to have satisfactory ability to predict both in-hospital mortality, with an area under the curve (AUC) of 0.76 (95% confidence interval [CI], 0.57-0.95; p = 0.014), and 6-month post-discharge mortality, with AUC of 0.78 (95%CI, 0.62-0.94), p = 0.002. The HL test indicated good-fit for both models of the GRACE score. Conclusion: In this study, the GRACE risk score for predicting mortality was appropriately validated in patients with ACS, with good discriminative power and goodness-of-fit. The results suggest that the GRACE score is appropriate for clinical use in our setting.

mortality or myocardial infarction so as to facilitate the stratification of patients with ACS.

Clinical outcomes
The primary outcome was defined as in-hospital and 6-month post-discharge mortality. With regard to secondary outcomes, the accuracy of the GRACE score was assessed in the different presentations of ACS.

Statistical analysis
Categorical data were presented as frequencies (percentages), and continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR). The Kolmogorov-Smirnov test was used to verify of distribution. The level of significance was set at p < 0.05 for all analyses. The discriminative power of the score with regard to in-hospital and 6-month post-discharge was assessed using the C statistics. The area under the receiver operating characteristic curve (AUC) represented the accuracy of the GRACE score in distinguishing survivors from non-survivors. Along with this analysis, cutoff values were identified to define the best prognostic sensitivity and specificity, with their 95% confidence intervals (CI). Goodness-of-fit for the scores was assessed by the Hosmer-Lemeshow test and by the dispersion graph between predicted mortality at each risk decile and the observed mortality. The analysis was performed using the SPSS 20.0, Minitab 16 and MedCalc, version 19.1 software.

Sample characteristics
The sample consisted of 160 patients. Two patients (1.25%) were lost to follow-up, due to absence of outpatient follow-up and telephone contact failure. Demographic and clinical characteristics with regard to the prevalence of cardiovascular risk factors and initial presentation are presented in Table 1. dichotomic ones: cardiac arrest at admission, ST-segment deviation, and elevation of cardiac markers. The final score can range from 0 to 372. 6 Therefore, the present study aimed to assess the value of the GRACE score as a predictor of in-hospital prognosis and 6-month post-discharge prognosis in patients with ACS in our setting.

Sample Selection
All individuals admitted with a diagnosis of ACS at Hospital de Clínicas de Passo Fundo (HCPF), Brazil, from May to December 2018 were selected. Demographic, clinical, and angiographic variables were prospectively collected. The patients were treated according to the criteria of the attending physician, without intervention from researchers. The study was approved by the Research Ethics Committee of Faculdade IMED, in compliance with the Resolution 466/2012 of the National Health Council.
Inclusion criteria were: age 18 years or older, symptoms suggestive of acute coronary ischemia on admission, and presence of at least one of the following characteristics: changes suggestive of ACS on electrocardiogram (ECG), elevation of serum biochemical markers of myocardial necrosis, and/or documented previous coronary artery disease with angiography showing coronary obstruction ≥ 50%. Patients whose ACS was triggered by secondary factors, such as trauma or surgery, were excluded. No patient refused to participate in the study, and all of them provided informed consent to participate in the research. Hospitalization outcomes were obtained by phone interview or outpatient visit 6 months after hospital discharge.

GRACE Score
The GRACE score was published in 2004 based on the GRACE registry, which was designed to reflect the full of patients with ACS. Data were obtained in 14 countries (Europe, North and South America, Australia, and New Zealand), including 94 hospitals, of which 6 were Brazilian, with a total population of 17142 patients. The aim of the score was to develop a tool to estimate of probability risk of 6-month

Primary outcome
In-hospital mortality was 5.1% (8 deaths). Six hospital deaths were caused by cardiogenic shock, and 2 by infectious complications with septic shock. The Hosmer-Lemeshow test for the in-hospital GRACE score yielded a c 2 of 7.14 (p = 0.522) and an AUC of 0.76 (95% confidence interval (CI), 0.57-0.95). Six-month post-discharge mortality was 7% (11 deaths). Among the patients who died after hospital discharge, 2 had sudden death, and 1 had a new episode of MI. The results for the 6-month post-discharge GRACE score showed c 2 of 4.53 (p = 0.81) and AUC of 0.78 (95%CI, 0.62-0.94). Therefore, both predictions exhibited a good-fit ( Figure 1).
According to the ROC curve, the best cutoff value for the in-hospital GRACE score was 179, with sensitivity of 50% and specificity of 98%. Conversely, the best cutoff value for the 6-month post-discharge GRACE score was 119.5, with sensitivity of 72.7% and specificity of 81.6% (Table 2).

Secondary outcome
The accuracy of the GRACE score in the different forms presentations of ACS was also tested. There was no outcome UA to be analyzed.
With regard to the non-ST segment elevation myocardial infarction (NSTEMI), mortality rate was 5.3%, all of which occurred during hospitalization. The in-hospital GRACE score had a c 2 of 5.96 (p = 0.425) and an AUC of 0.64. The cutoff value was 121.5, with sensitivity of 66.7% and specificity of 74.1%. Conversely, the GRACE score 6 months after discharge had a c 2 of 5.6 (p = 0.102) and an AUC of 0.59. The cutoff value was 98.5, with sensitivity of 66.7% and specificity of 63% ( Figure 2 and Table 3).
In the ST segment elevation myocardial infarction (STEMI), which had a mortality rate of 11.9%, the inhospital GRACE score had c 2 of 8.8 (p = 0.359) and an AUC of 0.78. The cutoff value was 179, with sensitivity of 80% and specificity of 91.9%. Conversely, the GRACE score 6 months after discharge, when cumulative mortality was 19%, had a c 2 of 7.99 (p = 0.435) and an AUC of 0.77. The cutoff value was 135, with sensitivity of 62.5% and specificity of 88.2% (Figure 2 and Table 3).

Discussion
The use of score risk for stratification and prognostic is recommended in the clinical practice by the national and international guidelines on NSTEMI and STEMI. 3,5 The GRACE score includes quantitative and qualitative variables and has greater discriminative accuracy than other prognostic tools, such as the TIMI risk. 3  In our setting, in-hospital mortality was 5.1%.
However, it was 2.8%, 2% and 13.9% for patients with predicted low, moderate, and high mortality risk, respectively. In the Spanish study with 6997 participants conducted by Cordero et al., mortality rate was 5.33% and 0%, 0.6% and 9.6%, respectively. 11 Even with a smaller In-hospital 6-month post-discharge

In-hospital
In-hospital 6-month after discharge 6-month after discharge sample, our study found values similar to those obtained in the Spanish study.
The limitation of our study is the fact that there was no exploratory analysis either of the factors related to mortality in our sample or of the impact of the prescribed pharmacological and interventional treatments.
It is the first Brazilian study that showed the validity of the GRACE score beyond in-hospital prognosis.

Conclusion
The GRACE score was validated to predict inhospital and 6-month post-discharge mortality in our setting in a non-selected sample of patients with ACS. The discriminative power of the score was found to be satisfactory, ratifying recent guidelines that recommend using the GRACE score in risk stratification and selection of intensive early treatment strategies, as well as in the watchful postdischarge follow-up.

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 thesis or dissertation work.

Ethics approval and consent to participate
This study was approved by the Ethics Committee of the Faculdade Meridional -IMED under the protocol number 2.531.453. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.